CA2283575A1

CA2283575A1 - Combination therapy employing ileal bile acid transport inhibiting benzothiepines and hmg co-a reductase inhibitors

Info

Publication number: CA2283575A1
Application number: CA002283575A
Authority: CA
Inventors: Robert E. Manning; Kevin C. Glenn; Bradley T. Keller
Original assignee: Individual
Current assignee: GD Searle LLC
Priority date: 1997-03-11
Filing date: 1998-03-10
Publication date: 1998-09-17
Also published as: NO994390L; WO1998040375A2; IL131872A0; NZ337830A; BG103793A; SK125099A3; NO994390D0; WO1998040375A3; AU730024B2; PL336415A1; RU2247579C2; AU6440898A; CN1255864A; HUP0002395A2; EP0971744A2; HUP0002395A3; MXPA99008417A; AU730024C; BR9808013A; JP2002500628A

Abstract

Provided are novel benzothiepines, derivatives, and analogs thereof;
pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals. Also provided are compositions and methods for combination therapy employing ileal bile acid transport inhibitors and HMG Co-A reductase inhibitors for the treatment of hyperlipidemic conditions.

Description

DEMANDES OU BREVETS VOLUMlNEUX

COMPREND PLUS D'UN TOME.
CECI EST LE TOME ~ DE
NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPL1CAT10NSlPATENTS
THiS SECTION O>= THE APPL.1CATlON/PATENT CONTAINS MORE
THAN ONE VOLUME -THIS IS VOLUME OF
' NOTE: For additional volumes-pi~ase contact the Canadian Patent Office' -COMBINATION THERAPY EMPLOYING ILEAL BILE ACID TRANSPORT
INHTBITING BENZOTHIEPINES AND HMG Co-A REDUCTASE INHIBITORS
This application claims the benefit of priority of U.S. provisional application Serial No. 60/040,660, filed March 11, 1997. This application is also a continuation-in-part application of U.S. Serial No. 08/831,284, filed March 31, 1997, which is a continuation application of U.S. Serial No. 08/517,051, filed August 21, 1995, which is a continuation-in-part application of U.S. Serial No.
08/305,526 filed September 12, 1994; and is a continuation-in-part application of U.S. Serial No.
08/816,065, filed March 11, 1997, which claims priority from U.S. provisional application Serial No. 60/013,119, filed March 11, 1996.
BACKGROUND OF THE INVENTION
Field of the Invention The present invention relates to novel benzothiepines, derivatives and analogs thereof, in combination with HI~IG Co-A reductase inhibitors, pharmaceutical compositions containing them, and use of these compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia, in mammals.
Description of Related Art It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the circulation of bile acids within the lumen of~the intestinal tract is found to reduce the levels~of serum cholesterol in a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of atherosclerosis. Stedronsky, in "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties," Hiochimica et Bio_phvsica Acta, 1210 (1994) 255-287 discusses the biochemistry, physiology and known active agents ' surrounding bile acids and cholesterol.
Pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans by Heub_i, J.E., et al. See "Primary Bile Acid Malabsorption: Defective in Vitro Ileal Active Bile Acid Transport", Gastroenteroloav, 1982:83:804-11.
In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation (Reihner, E. et al, in °Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients", Journal of Lipid Research, Volume 31, 1990, 2219-2226 and Suckling el al, "Cholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatment", Atheroscleros~s, 89(1991) 183-190). This results in an increase in liver bile acid synthesis by the liver using cholesterol as well as an upregulation of the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels.
In another approach to the reduction of recirculation of bile acids, the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors (Kramer, et al, "Intestinal Bile Acid Absorption" The Journa~~of Hiolouical Chemi~t~-..~ Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993).
o~, In a series of patent applications, eg Canadian Patent Application Nos. 2,025,294; 2,078,588;

2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731, Hoechst Aktiengesellschaft discloses polymers of various naturally occurring constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and', in particular for use as hypocholesterolemic agents.
In vitro bile acid transportinhibition is disclosed to show hypolipidemic activity in The Wellcome Foundation Limited disclosure of the world patent application number WO 93/16055 for "Hypolipidemic Benzothiazepine Compounds"
Selected benzothiepines are disclosed in world patent application number W093/321146 for numerous uses including fatty acid metabolism and coronary vascular diseases.
Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of atherosclerosis as disclosed by application Nos. EP
508425, FR 2661676, and WO 92/18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring of the fused bicyclo benzothiepine ring.
The above references show continuing efforts to find safe, effective agents for the prophylaxis and treatment of hyperlipidemic diseases and their usefulness as hypocholesterolemic agents.
Additionally selected benzothiepines are disclosed ' for use in various disease states not within the present invention utility. These are EP 568 898A as abstracted by Derwent Abstract No. 93-351589; WO
89/1477/A as abstracted in Derwent Abstract No. 89-370688; U.S. 3,520.891 abstracted in Derwent 507018-B;
US 3,287,370, US 3,389,144; US 3,694,446 abstracted in Derwent Abstr. No. 65860T-B and WO 92/18462.
HMG Co-A reductase inhibitors have been used as cholesterol-lowering agents. This class of compounds inhibits 3-hydroxy-3-methylglutaryl-coenzymE A (HMG Co-A) reductase. This enzyme catalyzes the conversion of HMG Co-A to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.
' Benzothiazepine anti-hyperlipidemic agents are disclosed in WO 94/18183, WO 94/18184, WO 96/05188, WO
96/16051, AU-A-30209/92, AU-A-61946/94, AU-A-61948/94, and AU-A- 61949/94.
The present invention furthers such efforts by providing novel pharmaceutical compositions and methods for the treatment of hyperlipidemic conditions.
SUN~IARY OF THE INVENTION
Accordingly, among its various apects, the present invention provides compounds of formula (I):
O
J R' _S~ R8 R' ~R~a I ~ ~ ~ 3 ~\ ( I >

n R3 Rs \ 5 Ra R
wherein:
q is~an integer from 1 to 4;
n is an integer from 0 to 2;' R1 and R2 are independently selected from~the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and ° cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR9, ~9R1 ~ , N'R'Rl°RWA~ , SR9. S+R9R1~A~ p'R'Ri°RuA- ~ S _( 0 ) R9 . S02 R9 .
S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)a~yl, and cycloalkyl _ optionally have one or more carbons replaced by O, NR9, N+R9R10A-, S, SO, 502, S+R9A-, P+R9Rl0A-, or phenylene, wherein R9, R10, and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or Rl and R2 taken together with the carbon to which they are attached form C~-C1° cycloalkylidene;
R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycTe;~ldR9, NR9R10, SR9, S(O)R9, S02R9, and S03R9, wherein R' and Ri° are as defined above; or R3 and R4 together form =0, =NOR11, =S, =~g11R12, =NR9, or =CRZZR12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, car 1 icyalkyl, carboalkoxyalkyl,~
cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S(O)R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, S

wherein R9 and R10 are as defined above, provided that both R3 and R4 cannot be OH, NH2,and SH, or R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;
R5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heter cy~ e~quaternary heterocycle, quaternary ~heteroaryl, SR9,S(O)R9, S02R9, and S03Rg, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, hete~roaryl, heterocycle,/~quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,heteroaryl arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NRI3R14~ SR13~ S(O)R13~
S02R13, S03R13, NR130R14, NR13NR14R15~ N02, C02R13, CN, OM, S020M, S02NR13R14, C(O)NR13R14, C(O)OM, COR13, P (O) R13R14~ P+R13R14R15A_~ P (OR1') ORI~, S'R1'R"A-, and N+R9R11R12A
wherein:
A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, ~t~cycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of ORS, NR~RB, SRS, S(O)RB, S02R~, S03R~,,C02R~, CN, ~o~co, CONR~R8, N+R~R8R9A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, hetezoazyl, azylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R~Ra, P+R~R8R9A , and P(0)(OR~)OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether , aryl , haloalkyl , cycloalkyl , hetemcycle and heteroaiyl can optionally have one or more carbons replaced by 0, NR~, N+R~R8A-, S, SO, S02, S+R~A-, PRA. P(0)R~.
P+R~R8A-, or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, hetexoaryl, heterocycle,~ and polyalkyl optionally have one or more carbons replaced by 0, NR', N+R9R10A-, S, S0, S02, S+R9A , PR9, P+R9R10A-, P(O)R', phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13~ R14~ and R15 are optionally substituted with one or more groups selected from the group consisting of sulf a7.tkcqua erna ~
ry heterocycle, quaternary heteroaryl, OR9, NR9R10, N+R9R11R12A , SR9. S(0)R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NRgR10, p0(OR16)ORl~, P+R9R10R11A-~ S+R9R10A-~ and C(O)C~'I.
wherein R16 and R1~ are independently selected from the substituents constituting R9 and M; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring;
R~ and RB are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl~
polyether, quaternary heterocycle, quaternary heteroaryl, OR13, ~13R14~ SR13, S(O)R13, S(0)2R13, S03R13, S+R13R14A-~ ~130R14~ ~13~14R15~ N02. C02R13, CN, OM, S020M, S02NR13R14 ~ ~1.C (0) R1', C (O) NR13RI4 NR14C(O)R13, C(0)OM, COR13, OR18, S(O)nNRlB, ~13R18~
~180R14~ N+R9R11R12A-~ P+R9R11R12A-~ amino acid, peptide, polypeptide, and carbohydrate, - wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, h teroaxyl, polyalkyl, heterocycle,n acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N+R9R11R12A-, SR9, S(O)R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NR9R10, PO(OR1')OR1', P+R9R11R12A-, S'R'R1°A-, or C (O) OM, and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heter~oa=yl, alkyl, quaternary heterocycle, and quaternary heteroaryl wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyh quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substita.st~ selected from the group consisting of OR9, NR9R10, N+R9R11R12A-~ SR9, S(0)R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S03R9, S020M, S02NR9R10, PO(OR16)OR1~, and C(O)OM, wherein in Rx, one or more carbons are optionally replaced by O, NR13, N+R13R14A-~ S, S0, S02, S+R13A-, PR13, ~ p(0)R13 P+R13R14A-~ phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR9, N+R9R10A-, S, SO, S02, S+R9A-, PR9, P+R9R10A-, or P(O)R';
wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, ~haloalkyl, cycloalkyl, heterocyc e,n li-ylalkyl, halogen, oxo-, OR13, NR13R14, SR13, S(O)R13, S02R13, S03R13, NR130R14, NR13NR14R15, N02. C02R13, CN, OM, S020M, S02NR13R14~ C(0)NR13R14~ C(0)OM, COR13, p(O)R13R14~
P+R13R14R15A_~ p(ORIS)OR1', g'Rl'R~'A , and N+R9R11R12A-provided that both R5 and R6 cannot be hydrogen, OH, or SH~and when R5 is OH, R1, R2, R3, R4, R~ and R8 cannot be all hydrogen;
provided that when R' or R' is phenyl, only one of R1 or R= is H;
provided that when q = 1 and R" is styryl, anilido, or anilinocarbonyl, only one of R' or R' is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Preferably, RS and R6 can independently be selected from the group consisting of H, aryl, heterocyc e,~ a'ternary heterocycle, and quaternary heteroaryl, wherein said aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be.
- 30 substituted with one or more subs'tituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, hetero~~rc~e,'larylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(O)R13,~S~02R13, S03R13, NR130R14~ ~I3NR14R15~ N02, C02R13, CN, OM, S020M, S02NR13R14~ C(O)NR13R14~ C(O)OM,,COR13, p(O)R13R14~
P+R13 R14.R15A- ~ p ( OR1' ) OR1' , S+Rl'R~.A- ~ and N+R9R11R12A-wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and het~yl can optionally have one or more carbons replaced by O, NR~, N+R~R8A-, S, SO, S02, S+R~A-, PRA, P(O)RE
~P+R~R8A-, or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and he~yl can be further substituted with one or more substituent groups selected from the group consisting of ORS, NR~R8, SRS, S(O)RB, S02R~, S03R~, C02R~, CN, oxo, CONR~R8, N+R~R8R9A-, alkyl, alkenyl, alkynyl, aryl, hete~aryl, cycloalkyl, heterocycle,narylalkyl, quaternary heterocycle, quaternary heteroaryl, P (O) R~RB, P+R~R8RgA-, and P ( O ) ( OR' ) OR° .
More preferably, RS or R' has the formula:
-Ar- ( RY ) t wherein:
t is an integer from 0 to 5;
Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, .isoquinolinyl, quinoxalinyl, isnidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl,~benzoimidazolyl.
benzoxazolyl, benzothiazolyl, and benzoisothiazolyl;
and one or more Ry are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, ~t~~,l, quaternary heterocycle.
,, quaternary heteroaryl OR9, SR9, S(O)R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkvl.
_ heterocycle, and heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, he~yl.
arylalkyl, halogen, oxo, OR13, ~13R14~ SR13~ S(0)R13~
.S02R13. S03R13, NR130R14, NR13NR14R15, N02. C02R13, CN, OM,.S020M, S02NR13R14~ C(0)~13R14~ C(O)OM, COR13, P (0) R13R14 ~ p+R13R14R15A_ ~ p (OR1') OR1', S'R1'R"A-, and N+R9R11R12A-wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,~~. aid heGa~a~Yl can be further substituted with one or more substituent groups selected from the group consisting of ORS, NR~R8, SRS, S(O)RB, S02R~, S03R~, C02R~, CN, oxo, CONR~R8, N+R~R8R9A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, he~yl, a~y7allcyl, g_sb~y heterocycle, quaternary heteroaryl, P (0) R~R8, P R~RBF~A-, and P ( 0 ) ( OR' ) ORS , and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, and heteroaryl can optionally have one or more carbons replaced by 0, NR~, N+R~RBA-, S, S0, 502, S+R~A-, PRA, P(O)R', P+R~RBA-, or phenylene._ Most preferably, RS or R6 has the formula (II):

(II) (Ry)t The invention is further directed to a compound selected from among:
Rio - R19 - Ru (Formula DI) R"

R - R - R (Formula DII), and R~=
2 0 Rso - R19 - Rsl (Formula DIII) R~' wherein Rl' is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide, wherein alkane diyl,~alkene diyl,.alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can optionally have one or more carbon atoms replaced by O, NR~, N+R~RB, S, SO, S02. S+R~R8,.
~a PRA, P+P~R8, phenylene, heterocycle, heteroaryl, quatern~yy heterocycle, quaternary heteroaryl, or aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, . 5 polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with oae or more aubetituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,heteroaryl, arylalkyl, halogen, oxo, OR13, ~13R14~ SR13~ s~0)R13~
sOZRl3, so3Rl3, NAl3oRl4, NR13NR14R15~ Via. COZR13, cN.
OM, SOZOM, S02NRl'~R14, C(O)NR13R14, C(O)OM, COR13, P (O) R13R14 ~ ptR13R14.R15A_ I p (OR" ) OR", S'R"RmA., and NtR9R11R12A ~
wherein R" further comprises functional linkages by which R'.' is bonded to R'°, R", or R" in the compounds of Formulae DII and DIII, and R" in the compounds of Formula DIII. Each of R'°, R", or R" and R" comprises a benzothiepine moiety as described above that is therapeutically'effective in inhibiting ileal bile acid transport.
The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula DIII in which each of R", R", R" and R" comprises a benzothiepine moiety corresponding to the Formula:
(off tR'~ ' a ~ (Formula DIY) ar:

(Oh R7 (RX~
(Formula DIVA) wherein R', R', R', R', Rs, R', R', R°, R", q, and n are as defined in Formula I as described above, and R's is either a covalent bond or arylene.
In compounds of Formula DIV, it is particularly preferred that each of R'°, R", and R" in Formulae DII
and DIII, and R" in Formula DIII, be bonded at its 7-or 8-position to R". In compounds of Formula DIVA, it is particularly preferred that Rs' comprise a phenylene moiety bonded at a m- or p-carbon thereof to R".
Examples of Formula DI include:
Re R~ R2 ..
R~~ ~~ Rs -..

,e (III) (R'~q (R'u°,)r 4~

;3A
R~ ~~' (IV) RBA
,. . ,q _ . ' ~n R
O O
d a and (R
R8 Ri R2 R4A
R7~ ~ R3 RsA
Ra R~s~ ~ R2A
(v) --. ' RBA
g Ren (R"A)~ ' RBA
O
~R~c a (R'~q In any of the dimeric or multimeric structures discussed~immediately above, benzothiepine compounds of the present invention can be used'alone or iri various combinations.
In any of the compounds of the present invention, R1 and R' can be ethyl/butyl or butyl/butyl.

Other compounds useful in the present invention as ileal bile acid transport inhibitors are shown in Appendix A.
In another aspect, the present invention provides a pharmaceutical composition for the prophylaxis or treatment of a disease or condition for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis.
Such compositions comprise any of the compounds disclosed above, alone or in combination, in an amount effective to reduce bile acid levels in the blood, or to reduce transport thereof across digestive system membranes, and a pharmaceutically acceptable carrier, excipient, or diluent.
In a further aspect, the present invention also provides a method of treating a disease or condition in mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising administering to a patient in need thereof a compound of the present invention in an effective amount in unit dosage form or in divided doses.
In yet a further aspect, the present invention also provides processes for the preparation of compounds of the present invention.
In yet another aspect, the present invention provides a combination therapy comprising the use of a first amount of an ileal bile acid transport.inhibitor and a second amount of a HMG Co-A reductase inhibitor useful to treat hyperlipidemic disorders, wherein said first and second amounts together comprise an anti-hyperlipidemic condition effective amount of said compounds.
HMG Co-A reductase inhibitor~compounds useful in the present invention are shown in Appendix B.-.
Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be tb understood that the following detailed dscription and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will beomce apparent to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the emobadiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.
The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference in their entirety.
Definitions In order to aid the reader in understanding the following detailed description, the following definitions are provided:
"Alkyl", "alkenyl," and "alkynyl" unless otherwise noted are each straight chain or branched chain hydrocarbons of from one to twenty carbons for alkyl or two to twenty carbons for alkenyl and alkynyl in the present invention and therefore mean, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl,and ethenyl, propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexyriyl - respectively and isomers thereof.
"Aryl" means a fully unsaturated mono- or multi-ring carbocyle, including, but not limited to, I~

substituted or unsubstituted phenyl, naphthyl, or anthracenyl.
"Heterocycle" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms can be replaced by N, S, P, or 0. This includes, for example, the following structures:
Z
i-~... ,-~ Z"' i ry ~ ~ ~ r ~
or Z
wherein Z, Z', Z" or Z"' is C, S, P, O, or N, with the proviso that one of Z, Z', Z" or Z"' is other than carbon, but is not O or S when attached to another Z
atom by a double bond or when attached to another 0 or S atom. Furthermore, the optional substituents are understood to be attached to Z, Z', Z" or Z"' only when each is C.
The term "heteroaryl" means a fully unsaturated heterocycle.
In either "heterocycle" or "heteroaryl," the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.
The term "quaternary heterocycle" means a heterocycle in which one or more of the heteroatoms, for example, O, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heterocycle to the molecule of interest can be at a heteroatom or elsewhere.
The term "quaternary heteroaryl" means a.
heteroaryl in which one or more of the heteroatoms, for example, O, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heteryaryl to the molecule of interest can be at a heteroatom or elsewhere.
I$

WO 98/40375 PCf/US98/03792 The term "halogen" means a fluoro, chloro, bromo or iodo group.
The term "haloalkyl" means alkyl substituted with one or more halogens.
The term "cycloalkyl" means a mono- or multi-ringed carbocycle wherein each ring contains three to ten carbon atoms, and wherein any ring can contain one or more double or triple bonds.
The term "diyl" means a diradical moiety wherein said moiety has two points of attachment to molecules of -interest.
The term "oxo" means a doubly bonded oxygen.
The term "polyalkyl" means a branched or straight hydrocarbon chain having a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.
The term "polyether" means a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the polyether has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.
The term "polyalkoxy" means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.
The term "cycloaklylidene" means a mono- or multi-ringed carbocycle wherein a carbon within the ring structure is doubly bonded to an atom which is not within the ring structures.
The term "carbohydrate" means a mono-, di-, tri-, or polysaccharide wherein the polysaccharide can have a molecular'weight of up to about 20,000, for example, - hydroxypropyl-methylcellulose or chitosan.
The term "peptide" means polyamino acid~c.ontaining up to about 100 amino acid units.
The term "polypeptide" means polyamino acid containing from about 100 amino acid units to about ~9 1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid untis, most preferably from about 100 amino acid units to about 500 amino acid units.
The term "alkylammoniumalkyl" means a NHz group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein said alkyl is bonded to the molecule of interest.
The term "triazolyl" includes all positional isomers. In all other heterocycles and heteroaryls which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocycles and heteroaryls.
The term "sulfoalkyl" means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.
The term "active compound" means a compound of the present invention which inhibits transport of bile acids.
When used in combination, for example "alkylaryl"
or "arylalkyl," the individual terms listed above have the meaning indicated above.
The term "a bile acid transport inhibitor" means a compound capable of inhibiting absorption of bile acids from the intestine into the circulatory system of a mammal, such as a human. This includes increasing the fecal excretion of bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL
and VLDL cholesterol. Conditions or diseases which benefit from the prophylaxis or treatment by bile acid transport~inhibition include, for example, a hyperlipidemic condition such as atherosclerosis.
The phrase "combination therapy" refers to the administration of an ileal bile acid transport inhibitor and a HMG Co-A reductase inhibitor to treat a hyperlipidemic condition, for example atherosclerosis ~,o and hypercholesterolemia. Such administration encompasses co-administration of these inhibitors in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent. In addition, such administration also encompasses use of each type of inhibitor in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the hyperlipidemic condition.
The phrase "theraputically effective° is intended to qualify the combined amount of inhibitors in the combination therapy. This combined amount will achieve the goal of reducing or eliminating the hyperlipidemic condition.
Compounds The compounds of the present invention can have at least two asymmetrical carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. Such stereoisomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.
Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds of the present invention.
The compounds of the present invention also include tautomers.
The compounds of the present invention as discussed below include their salts, solvates.and prodrugs.
compound syntheses a~

The starting materials for use in the preparation of the compounds of the invention are known or can be -prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art.
Generally, the compounds of the present invention can be prepared by the procedures described below.
For example, as shown in Scheme I, reaction of aldehyde II with formaldehyde and sodium hydroxide yields the hydroxyaldehyde III which is converted to mes~rlate IV with methanesulfonyl chloride and triethylamine similar to the procedure described in Chem. Ber. 98, 728-734 (1965). Reaction of mesylate IV
with thiophenol V, prepared by the procedure described in WO 93/16055, in the presence of triethylamine yields keto-aldehyde VI which can be cyclized with the reagent, prepared from zinc and titanium trichloride in refluxing ethylene glycol dimethyl ether (DME), to give a mixture of 2,3-dihydrobenzothiepine VII and two racemic steroisomers of benzothiepin-(5H)-4-one VIII
when R1 and R~ are nonequivalent. Oxidation of VII with 3 equivalents of m-chloro-perbenzoic acid (MCPBA) gives isomeric sulfone-epoxides IX which upon hydrogenation with palladium on carbon as the catalyst yield a mixture of four racemic stereoisomers of 4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxides X and two racemic stereoisomers of 2,3,4,5-tetrahydro-benzothiepine-1,1-dioxides XI when R1 and R= are nonequivalent.
Optically active compounds of the present invention can be prepared by. using optically active starting material III or by resolution of compounds X with optical resolution agents well known in the art as described in J.
Org. Chem., 39, 3904 (1974), ibid., 42, 2781 (1977), and ibid., 44, 4891 (1979).

Rt Rs --~. i~ip Rt Rs ~~ ~,rp Rt R:
- p ~ ~ 0 't 0 R R~ ~ R R8 N
~$ RtR
Rt R ~N '! s H
' R, ~ llio s , O
o se%
~I, ~R'~ R R' v N
w ~-, ~b ø, RS
Rt Rt ~ i. R= ~ ~ R=
O
z, ~a ~ooolls ~ACPSA ~ R ~ ~ R t R= li=lPd-C ~ ~ Rs ---~ --'-~, b fix) x Rt R
s CR )$
>e Alternatively, xeto-aldehyde VI where R' is H can be prepared by reaction of thiophenol V with a 2-substituted acrolein.

St! O ~ H
R R1 ~N H
s , ~ p O
~x~ ~; ~ R ~
H
Benzothiepin-(5H)-4-one VIII can be oxidized with MCPBA
to give the benzothiepin-(SH)-4-one-1,1-dioxide XII
Which can be reduced with sodium borohydride to give , four racemic stereoisomers of X. The two stereoisomers of X, Xa and Xb, having the OH group and R' on the opposite sides of the benzothiepine ring can be converted to the other two isomers of X, Xc and Xd, having the OH group and R'Ion the same side of the benzothiepine ring by reaction in methylene chloride with 40-50~ sodium hydroxide in the presence of a phase transfer catalyst (PTC). The transformation can also be carried out with potassium t-butoxide in THF.
~4 \ R' 2~ R ~s R: ~ Ra ~- ~ R:
x _ ~0 ~.~ .OH
((Z ~ t~ i x H
~t .,~~ ~t a0 R1 sp Rt ~'~ R:
...n.~~ R=
(~x~ . __ ~" ~ ..
R1 OOH,. PT~f~I =as ~L" R OH
t xs a t ~, Rt a0 Rt R~
~d R=
.wi R=
H
~s xs wiwnR ~~ Bu,R=~~,R ~~Ph,X~tl.q~4 e~ ~ Xr ~b ~ 7m 8c ~ xc Ed~Xd The compounds of the present invention where R' is OR, ' or S ~O)aR and R' is hydroxy can be prepared by reaction of epoxide IX where R' is H with thiol, alcohol, or amine in the presence of a base.
~S

R~ R1 ~ R' x S R=
~ R~ ~ v HOR, or HNRRI or HS(O) R base n R' Re S= R' ..~u Rt ~ R~ ~ ~ ~ Ohl R' - OR, NRRI, S(O)~R
Another route to Xc and Xd of the present invention is shown in Scheme 2. Compound VI is oxidized to compound XIII with two equivalent of m-chloroperbenzoic acid.
Hydrogenolysis of compound XIII with palladium on IO carbon yields compound XIV which can be cyclized with either potassium t-butoxide or sodium hydroxide under phase transfer conditions to a mixture of Xc and Xd.
Separation of Xc and Xd can be accomplished by either HPLC or fractional crystallization.

WO 98/40375 PCT/tJS98/03792 The thiophenols XVIII and V used in the present invention can also be prepared according to the Scheme 3. Alkylation of phenol XV with an arylmethyl chloride - s in a nonpolar solvent according to the procedure in ~T.
Chain. Soc., 2431-2432 (1958) gives the ortho substituted phenol XVI. The phenol XVI can be converted to the thiophenol XVIII via the thiocarbamate XVII by the procedure described in J. Org. Chem., 31, 3980 (1966). The phenol XVI is first reacted with dimethyl thiocarbamoyl chloride and triethylamine to give thiocarbamate XVII which is thermally rearranged at 200-300 °C, and the rearranged product is hydrolyzed with sodium hydroxide to yield the thivphenol XVIII.
Similarly, Thiophenol V can also be prepared from 2-acylphenol XIX via the intermediate thiocarbamate XX.
s~ 1 R I R1 R? ~~~ RI ~ p~? ~Y r R R.~.
1 ~ ~ ~ O~ ~ N Oy ~ N
2 ~, ~ WdIG
R5 ~ R5 ~ ~ 5 R
! ~R'~~c~ ~R''~~ ~~x~ xiv lCOtBu 1'1 R3 Y R~ R3 d RI SO RI
al R~ '~" ~~,ul ~~,~~ =RS off ~Rx,~ R~ off ~7 OH
f RaCti=d ~ Ra ~P~"~ XV CR~'~ XH

oJi- trw = t. 0 2 N~OH 8H
Ra I Ra ~ ~ R
/ /
CR"~ ~Rx~~ xvn m s O ~~ ~ ~ O
2~ ~ O
Ra ~, ~ / Ri ---~ ( ~ Ra ( R~~ me ~ g~ ~ roc CR~'~ ~
Scheme 4 shows another route to benzothiepine-1,1-dioxides Xc and Xd starting from the thiophenol XVIII.
Compound XVIII can be reacted with mesylate IV to give the sulfide-aldehyde XXI. Oxidation of XXI with two' equivalents of MCPBA yields the sulfone-aldehyde XIV
which can be cyclized with potassium t-butoxide to a mixture of Xc and Xd. Cyclyzation of sulfide-aldehyde with potassium t-butoxide also gives a mixture of benzothiepine XXIIc and XXIId.
~:8 _ 1H ~~ t~~ ~ Rs R, Rg Rt . ~ Rs Hs0 R1 ~ H a0= ~ H
~ Ri 'he 0 ~ct~X)$ " ~ i \'~ ~ ~ R
'~' "' CR")$ CRX~~
goo ~av IOD~u l~f8u ~,~~ R s R1 a0 Rt w~~n ."~1 R:
,"« ~
+ ~~/~/
Ctv )~ Rs :%OH CRX~~ Rs ON CR~i~ Rs SON
-~ x xo ' ~~ R s' R~
~~~111 R=
R, xe Examples of amine- and hydroxylamine-containing compounds of the present invention can be prepared~as shown in Scheme 5 and Scheme 6. 2-Chloro-5-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-5-nitrodiphenylmethane 3Z. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of - 10 XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV which can be reduced by hydrogenation to the hydroxylamine XXV. protecting the hydroxylamine XXV
with di-t-butyldicarbonate gives the N,D-di-(t-a~

butoxycarbonyl)hydroxylamino derivative XXVI.
Cyclization of XXVI with potassium t-butoxide and removal of the t-butoxycarbonyl protecting group gives a mixture of hydroxylamino derivatives XXVIIc and XXVIId. The primary amine XXXIIIc and XXXIIId derivatives can also be prepared by further hydrogenation of XXIV or XXVIIc and XXVIId.

s~ s a Ct O
_ r_ 1 ~s NOZ 3: NOx - ~ p' Z~eJsloco-s-V
nitx~a~a~e . iv p2 2 Yc~ ~ p2 S
~ I
HZ NOZ ~ N70mr Hs'~1C
R~ p2 csa~o I N(HOC)O(HOG~
1 pu~am c-butopde~ NHOH ~y 2 add ~
~, O
l Qs O
HOHN i ~~ ' E''~ R
Ph OH HOHN Ph OH
JoNad Rvc-x~ ioo ~, x ~c ~cxz.ioo ~, so ~c Q, o p,~ Q, O
~ ~t + pt H2N i az Ph OH H2N OH
Ph In Scheme 6, reduction of the sulfone-aldehyde XXV
with hydrogen followed by reductive alkylation of the resulting amino derivative with hydrogen and an aldehyde catalyzed by palladium on carbon in the same reaction vessel yields the substituted amine derivative a H~ooH
o-~ ~ ~

XX~/ ~~ 70No IOD~eu hf r ~o 'aN
N ~ OH
XXVIII. Cyclization of XXVIII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention XXIXc and XXIXd.
Scheme 7 describes one of the methods of introducing a substituent to the aryl ring at the 5-position of benzothiepine. Iodination of 5-phenyl l0 derivative XXX with iodine catalyzed by mercuric triflate gives the iodo derivative XXXI, which upon palladium-catalyzed carbonylation in an alcohol yields the carboxylate XXXII. Hydrolysis of the carboxylate 3~

8dmer T
v ~ ° ~'~ 6 _ o ''~ rt, R, Ho(~ s »u111 R= .
t= . 2s C
N
II \/
Pd a~y~
° ~.~ CQI R~OH

I
N
~0a1 and derivatization of the resulting acid to acid derivatives are well known in the art.
Abbreviations used in the foregoing description have the following meanings:
TfiF---tetrahydrofuran PTC---phase transfer catalyst Aliquart 336---methyltricaprylylammonium chloride MCPBA---m-chloroperbenzoic acid Celite--- a brand of diatomaceous earth filtering aid DMF---dimethylformamide DME----ethylene glycol dimethyl ether BOC---t-butoxycarbonyl group Rl and R' can be selected from among substituted and unsubstituted C1 to Cla alkyl wherein the substituent(s) can be selected from among alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocycles joined to the Ci to Clo alkyl through an ether linkage. Substituents at the 3-carbon can include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, i sopropyl , -CHzC ( =O ) C~HS , -CHzOCzHs , and -CH=0- ( 4 -picoline). ~thyl, n-propyl, n-butyl, and isobutyl are preferred. In certain particularly preferred compounds of the present invention, substituents R1 and RZ are identical, for example n-butyl/n-butyl, so that the compound is achiral at the 3-carbon. ~liminating optical isomerism at the 3-carbon simplifies the selection, synthesis, separation, and quality control of the compound used as an ileal bile acid transport inhibitor. In both compounds having a chiral 3-carbon and those having an achiral 3-carbon, substituents (R") on the benzo- ring can include hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N)-hydroxy-carbonylalkyl amine, haloalkylthio, haloalkylsulfinyl, haloalkylsufonyl, amino, N-alkylamino, N,N-dialkylamino, (N)-alkoxycarbamoyl, (N)-aryloxycarbamoyl, (N)-aralkyloxycarbamoyl, trialkyl-ammonium (especially with a halide counterion), (N)-amido, (N)-alkylamido, -N-alkylamido, -N,N-3'~

dialkylamido, (N)-haloalkylamido, (N)-sulfonamido, (N)-- alkylsulfonamido, (N)-haloalkylsulfonamido, carboxyalkylamino, trialkyl-ammonium salt, (N)-carbamic _ acid, alkyl or benzyl ester, N-acylamine, hydroxylamine, haloacylamine, carbohydrate, thiophene a trialkyl ammonium salt having a carboxylic acid or hydroxy substituent on one or more of the alkyl substituents, an alkylene bridge having a quaternary ammonium salt substituted thereon, -[O(CH,)'"]x-X where x is 2 to 12, w is 2 or 3 and X is a halo or a quaternary ammonium salt, and (N)-nitrogen containing heterocycle wherein the nitrogen of said heterocycle is optionally quaternized. Among the preferred species which may constitute R" are methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamine, N-methylamino, N,N-dimethylamino, N,N-diethylamino, (N)-benzyloxycarbamoyl, trimethylammonium, A, 2 0 -NHC ( =0 ) CHI , -NHC ( =O ) CSHI~ , -NHC ( =O ) C6H1, , carboxyethylamino, (N)-morpholinyl, (N)-azetidinyl, (N)-N-methylazetidinium A~, (N)-pyrrolidinyl, pyrrolyl, (N)-N-methylpyridinium A , (N)-N-methylmorpholinium A , and N-N'-methylpiperazinyl, (N)-bromomethylamido, (N)-N-hexylamino, thiophene, -N'(CH~)~COzH I~, -NCHsCH=COSH, -(N)-N'-dimethylpiperazinium I-, (N)-t-butyloxycarbamoyl, (N)-methylsulfonamido, (N)N'-methylpyrrolidinium, and - (OCHZCH~) ~I, where A' is a pharmaceutically acceptable anion. The benzo ring can be mono-substituted at the 6, 7 or 8 position, or disubstituted at the 7-and -8 positions. Also included are the 6,7,8-trialkoxy compounds, for example the 6,7,8-trimethoxy compounds. A variety of other substituents can be advantageously present on the 6, 7, 8, and/or 9- positions of the benzo ring, including, for example, guanidinyl, cycloalkyl, carbohydrate (e.g., a 5 or 6 carbon monosaccharide), peptide, and i quaternary ammonium salts linked to the ring via poly ( oxyalkylene ) 1 inkages , a . g . , - ( OCHzCHs ) x-N~RI'R1~R~SA-, where x is 2 to 10. Exemplary compounds are those set forth below in Table 1.
3~

WO 9$140375 PCTIUS98/03792 Alt eraative compcuads $3 (Fa=..: ly F101. xxx . yyyj - 0~ i0 ~z) i s ~ S ~ ..,... R2 R
.. ~~~ OFi R
pre;'-s C5~* Rl=A2 Rg ' (~ ' F.s~. vw) t 101. OQ'- n-propy'- P!:- 7-w~C::yI

02 n-p=opy'- Pr- 7-et:wl 03 a-propyi P::- 7-iso-p_opyl 04 n-p~apyl Ph- 7-tee -~L~p OS n-propy= Ph- 7-0::

06 n-p;opv~ Ph- 7-ccs3 07 n-gropyl Pa- 7-0(-so-~:Opy!) OS n-psopyl Ph- 7-SC'.-'.3 09 n-propy? P::- 7-SCGa3 It-p~opyl Ph- 7-S02Gs3 * General Notes In the description of the substituents '(N)' indicates that a nitrogen bearing substituent is bonded to the rinc structure via the nitrvgen'atom. -Similarly, 2-thiophene indicates a bond in the 2 position of the thiophene ring. A similar convention is used for other heterocyclic substituents.
Abbreviations and Definitions NFi-CBZ is defined as -HNC (=O) OCIiZPh 11 n-propyl Ph- 7-SCH2CH3 12 n-propyl Ph- 7-NH2 13 n-propyl Ph- 7-NHOH

14 n-propyl Ph- 7-NHCH3 15 n-propyl Ph- 7-N(CH3)2 16 n-propyl. Ph- 7-N+(CH3)3, I

17 n-progyl Ph- 7-NHC(-0)CH3 18 n-propyl Ph- 7-N(CH2CH3)2 19 n-propyl Ph- ?-NMeCH2C02H

20 n-propyl ph- 7-N'(Me)~CH2C02H, I-21 n-propyl ph- 7-(N)-morpholine 22 n-propyl Ph- 7-(N)-azetidine 23 n-propyl Ph- 7-(N)-N-ssethylazetidinium, I-24' n-propyl Ph- ?-(N)-pyrrolidine 25 n-propyl Ph- 7- (N) -N-methyl-pyrrolidiniu.-.t, I-26 n-prooyl Ph- 7-(N)-N-methyl-morpholiniu.-a, I' 27 n-propyl Ph- 7-(N)-N'-methylpiperazine 28 n-propyl Ph- 7-(N)-N'-dia:ethylpiperaziniL-z, I' 29 n-propyl Ph- 7-NL-CBZ

30 n-propyl Ph- 7-N~e(0)C5H11 31 n-gropyl Ph- 7-NYC(0)CH28r 32 n-propyl Ph- 7-NH-C(NH)NH2 33 n-propyl Ph- 7-(2)-thiophene 34 n-propyl Ph- 8-methyl 35 a-propyl Ph- 8-ethyl 36 n-propyl Ph- 8-iso-propyl 37 n-propyl Ph- 8-tent-butyl 38 n-propyl Ph- 8-OH

39 n-propyl Ph- 8-OCH3 40 n-propyl Ph- 8-0(iso-propyl) 41 n-propyl Ph- 8-SCH3 42 n-propyl Ph- 8-SOCH3 43 n-propyl Ph- 8-S02CH3 44 n-propyl Ph- 8-SCH2CH3 45 a-propyl Ph- 8-NH2 46 n-propyl Ph- 8-NHOH

47 n-propyl Ph- 8-NHCH3 48 a-propyl Ph- 8-N(CH3)2 49 n-propyl Ph- 8-N~fCH3)3, I-50 n-pzopyl Ph- B-NHC(~Q)CH3 51 n-propyl Ph- 8-N(CH2CH3)2 52 a-propyl Ph- 8-NMeCH2COZH

3~

53 n-propyl Ph- 8-N~ (Me) =CH2C02H~~'~1T

54 n-propyl Ph- 8-(N)-morpholine 55 n-propyl Ph- 8-(N)-azetidine - 56 n-propyl Ph- 8-(N)-N-methylazetidinium I-57 n-ProPyl Ph- , 8-(N)-pyrrolidine - 58 n-propyl Ph- 8-(N)-N-methyl-pyrrolidinium Z' 59 n-propyl Ph- , 8-(N)-N-methyl-morpholinium Z' 60 n-propyl Ph- , 8-(N)-N'-methylpiperazine 6i n-propyl Ph- 8-(N)-N'-dimethylpiperazinium Z-62 n-propyl Ph- , 63 n-propyl Ph- 8-NHC(O)C5H11 64 n-propyl Ph- 8-NHC(0)CH2Hr 65 n-propyl Ph- 8-NH-C(NH)NH2 66 n-propyl Ph- 8-(2)-thiophene 67 n-propyl Ph- 9-methyl 68 n-propyl Ph- 9-ethyl 69 n-propyl Ph- 9-iso-propyl 70 n-propyl Ph- 9-tent-butyl 71 n-propyl ph_ ~.-72 n-propyl Ph- 9-OCH3 73 n-propyl Ph- 9-O(iso-propyl) 74 n-propyl Ph- 9-SCx3 75 n-propyl Ph- 9-SOCH3 76 n-propyl Ph- 9-S02C::3 77 n-propyl Ph- 9-SCH2CH3 78 n-propyl Ph- 9-Nv2 79 n-propyl Ph- 9-NHOH

80 n-propyl Ph- 9-NHCH3 8I n-propyl Ph- 9-N(CH3)2 82 n-propyl Ph- 9-N+(CH3) I-83 n-propyl Ph- 3.
9-NHC(~0)CH3 84 n-propyl Ph- 9-N(CH2CH3)2 85 n-propyl Ph- 9-NMeCH2C02H

86 n-propyl Ph- 9-N(Me)ZCH2C02H, I-87 n-propyl Ph- 9-(N)-morpholine 88 n-propyl Ph- 9-(N)-azetidine 89 n-propyl Ph- g-(N)-N-methylazetidiniuin Z-90 n-propyl Ph- , 9-(N)-pyrrolidine 91 n-propyl Ph- 9-(N)-N-methyl-pyrrolidiniuas, I-92 n-propyl Ph- 9-(N)-N-methyl-morpholinium, Z-93 n-propyl Ph- 9-(N)-N'-methylpiperazine 93 n-propyl Ph- 9-(N)-N-d~thylpiperazinium, I-95 n-propyl ph- 9-NH-C82 96 n-propyl Ph- 9-NHC(0)C5H11 97 n-propyl Ph- 9-NHC(0)CH28r g8 n-propyl Ph- 9-NH-C(NH)NH2 gg n-pzopyl Ph- 9-(2)-thioghene 100 n-propyl Ph- 7-oCH3, 8-OCH3 101 n-propyl Ph- 7-SCH3, 8-OCIi3 I02 n-propyl Ph- 7-SCH3, 8-SCH3 103 n-pronvl Ph- 6-OCH3, 7-OCH3, 8-OCH3 Bzetis Cpd~ Rl=R2 RS (Rx)q (FFF s~ ~ wv) r10I.002 Ol n-butyl Ph- 7-rethyl _ 02 n-butyl Ph- 7-ethyl 03 n-butyl Ph- 7-iao-propyl 04 n-butyl Ph- 7-tent-5uty1 OS n-butyl Ph- 7-OH

06 n-butyl Ph- 7-OCH3 07 n-butyl Ph- 7-t~(iso-propyl) 08 n-butyl Ph- 7-~3 ..

09 n-butyl Ph- 7-SOC'.-'.3 n-butyl Ph- 7-S02CS3 11 n-butyl Ph- 7-SC:i2C 3 12 n-butyl Ph- 7-Nii2 13 n-butyl Ph- 7-NHOH

14 n-butyl Ph- 7-NF:C:~3 n-butyl Pr- 7-N (C:i3) 2 16 n-butyl Ph- 7-N+(Cv3)3. I

17 n-butyl Ph- 7-NHC(=0)CH3 18 n-butyl Ph- 7-:~ (CH2CH3) 2 lg n-butyl Ph- 7-N:leCHyC02H

n-butyl Ph- 7-N'(Me)ZCHZC02H, I-21 n-butyl Ph- 7-(N)-morpholine 22 n-butyl Ph- 7-(N)-azetidine 23 n-butyl Ph- 7-(N)-N-methylazetidinium, I' 24 n-butyl Ph- 7-(N)-pyrrolidine n-butyl Ph- 7-(N)-N-methyl-pyrzolidinium, I' 26 n-butyl Ph- 7-(N)-N-methyl-morpholinium, I' 27 n-butyl Ph- 7-(N)-N'-methylpiperazine 28 n-butyl Ph- 7-(N)-N'-dimethylpiperazinium, I' 29 n-butyl Ph- 7-NH-C9Z

n-butyl Ph- 7-NHC(0)CgHll 31 n-butyl Ph- 7-NHC(0)CH2Br L~..O

32 n-butyl Ph- 7-NH-C(NH)NH2 33 n-butyl Ph- 7-(2)-thiophene - 34 n-butyl Ph- 8-methyl 35 n-butyl Ph- 8-ethyl 36 n-butyl Ph- 8-iso-propyl - 37 n-butyl Ph- 8-tart-butyl 38 n-butyl Ph- 8-OH

39 n-butyl Ph- 8-OCH3 40 n-butyl Ph- 8-O(iso-propyl) 41 n-butyl Ph- 8-SCH3 42 n-butyl Ph- 8-SOCH3 43 n-butyl Ph- 8-S02CH3 44 n-butyl Ph- 8-SCH2CH3 45 n-butyl Ph- 8-NH2 46 n-butyl Ph- 8-NHOH

47 n-butyl Ph- 8-NHCh3 48 n-butyl Ph- 8-N(Ca3)2 49 n-butyl Ph- 8-~+(CH3)3. I' 50 n-butyl ph- 8 ~ ~ a v -H:C ( 0 ) C..3 51 n-butyl ph_ 8-N (Cu2CH3 ) 2 52 n-butyl Ph- 8-NMeCH2C02H

53 n-butyl Ph- 8-N (,!e) =Ca2C02H, I' 54 n-butyl Ph- 8-(N)-mo~roline 55 n-butyl Ph- 8-(N)-azetidine 56 n-butyl Ph- 8- (N) -N-~ ethylazetidiniu.-.t I' 57 n-butyl Ph- , 8-(N)-pyrrolidine 58 n-butyl Ph- 8-(N)-N-methyl-pyrrolidiai I-59 n-butyl Ph- um, 8-(N)-N-aethyl-morpholini I' 60 n-butyl Ph- uia, 8-(N)-N'-c~ethylpiperazine 61 n-butyl Ph- 8-(N)-N'-dimethylpiperazinium I' 62 n-butyl Ph- , 63 n-butyl Ph- 8-NHC(O)CSH11 64 n-butyl Ph- 8-NHC(0)CH28r 65 n-butyl Ph- 8-NH-C (NH) NH2 66 n-butyl Ph- 8-(2)-thiophene 67 n-butyl Ph- 9-methyl 68 n-butyl ~Ph- 9-ethyl 69 n-butyl Ph- 9-iso-propyl 70 n-butyl Ph- 9-tart-butyl 71 n-butyl ph- 9~H .

72 a-butyl ph- 9-~H3 73 n-butyl Ph- 9-0(iso-propyl) 4~

74 n-butyl Ph- 9-SCH3 75 n-butyl Ph- 9-SOCH3 76 n-butyl Ph- 9-502CH3 77 n-butyl Ph- 9-SCH2CH3 78 n-butyl Ph- 9-NH2 79 n-butyl Ph- 9-NHOH

80 n-butyl Ph- 9-NHCH3 81 n-butyl Ph- 9-N(CH3)2 82 n-butyl Ph- g-N+(CH3)3, I-83 n-butyl Ph- 9-NHC(-0)CH3 84 n-butyl Ph- 9-N(CH2CH3)2 85 n-butyl ~Ph- 9-NMeCH2C02H

86 n-butyl Ph- 9-N' (,!e) ZCH2C02H, I-87 n-butyl Ph- 9-(N)-morpholine 88 n-butyl Ph- 9-(N)-azetidine 8 n-butyl Ph- 9- (N) -N-methylazetidiniurs, 9 I' 90 n-butyl Ph- 9-(N)-pyrrolidine 91 n-butyl Ph- g- (N) -;~-~ ethyl-pyr rolidinis:ri, I' 92 n-butyl Ph- 9-(,~~) jN-~-ethyl-r..o_pholinium, I-93 n-butyl Ph- 9-(Nrj~-N'-r..ethylpiperazine 93 n-butyl Ph- g-(N)-N~-di-ethylpiperaziniu~, I' 95 n-butyl Ph- 9-NH-C3Z

96 n-butyl Ph- 9-NsC (0) C5:~11 97 n-butyl Ph- 9-Ni:C (0) C::23=

98 n-butyl Ph- 9-NE-C(NH)N82 99 n-butyl Ph- 9-(2)-thiophene 100 n-butyl Ph- 7-OCH3, 8-GCH3 101 n-butyl ph- 7-SCH3, 8-OCH3 102 n-butyl Ph- ~-SCH3, 8-SCH3 103 n-butyl Ph- 6-OCH3, 7-OCH3, 8-OCH3 pre~is Cpd~ R1~R2 R5 (Rz) q (1~'f'F' . sa . YYY) F101.003 O1 n-pentyl Ph- 7-methyl 02 n-pentyl Ph- 7-ethyl 03 n-pentyl ph- 7-iso-propyl 04 n-pentyl ph- 7 -tent-butyl 05 n-pentyl ph- 7~g 06 n-pentyl ph- 7-OCH3 07 n-pentyl Ph- 7-0(iso-propyl) 08 n-pentyl ph- 7-SCH3 09 n-pentyl ph- 7-SOCH3 n-pentyl Ph- 7-SO2CH3 11 n-pentyl Ph- 7-SCH2CH3 12 n-pentyl Ph- 7-NH2 13 n-pentyl ' Ph- 7-NHOH

14 n-pentyl Ph- 7-NHCH3 - 15 n-pentyl ph- 7-N(CH3)2 16 n-pentyl Ph- 7-N+ICH3)3, _-17 n-pentyl Ph- 7-N'dC(-0)CH3 18 n-pentyl Ph- 7-N(CHZCH3)2 19 n-pentyl Ph- 7-NMeCH2COyH

n-pentyl Ph- 7-N'(Me)=CH2C02H, I-- 2I n-pentyl Ph- 7-(N)-csorpho line 22 n-pentyl Ph- 7-(N)-azetidine 23 n-pentyl Ph- 7- (N) -N-methylazetidiniuri I-24 n-pentyl Ph- , 7-(N)-pyrrolidine n-pentyl Ph- 7-(N)-N-methyl-pyrrolidiniu.-z I-26 n-pentyl Ph- , 7-(N)-N-:.-.ethyl-~orpholiaium, I-27 n-pentyl Ph- 7-(N)-N'-rethylpiperazine 28 n-pentyl Ph- 7- (at) -N' -dig ethylpiperaziniu.~, I-29 n-pentyl Ph- 7-:~~'=~HZ ..

n-pentyl Ph- 7-N C (0) C5::11 31 n-pentyl Ph- 7-:~'.-C (0) C::23r 32 n-peatyl Ph- 7-NH-C (:li:) Ni:2 33 n-pentyl Ph- 7-(2)-thiophene 34 n-pentyl Ph- 8-methyl n-pentyl Ph- 8-ethyl 36 n-pentyl Ph- 8-iso-propyl 37 n-pentyl Ph- 8-tent-butyl 38 n-pentyl Ph- 8-OH

39 n-pentyl Ph- B-OCH3 n-pentyl Ph- 8-0(iso-propyl) 41 n-pentyl Ph- 8-SCH3 42 n-pentyl Ph- 8-SOCH3 43 n-pentyl Ph- 8-SOZCH3 44 n-pentyl Ph- 8-SCH2CH3 n-pentyl ph- 8-46 n-pentyl Ph- 8-NHOH

47 n-pentyl Ph- 8-NHCHg 48 n-pentyl ph- 8-N(CH3)2 49 n-pentyl Ph- 8-N+(CH3) 3 I-n-pentyl Ph- , 8-NHC(-0)CH3 51 n-pentyl Ph- 8-N(CHyCH3)2 52 n-pentyl Ph- 8-NMeCH2C02H

53 n-pentyl Ph- 8-N'(Me)2CH2C02H, I' 54 n-pentyl Ph- 8-(N)-morpholine 55 n-pentyl Ph- 8-(N)-azetidine 56 n-pentyl Ph- 8-(N)-N-methylazetidinium, I' 57 n-pentyl Ph- 8-(N)-pyrrolidine 58 n-pentyl Ph- 8-(N)-N-methyl-pyrrolidiniu:a, I' 5g n-pentyl Ph- 8-(N)-N-cethyl-morpholinium, I' 60 n-pentyl Ph- 8-(N)-N'-methylpiperazine 61 n-pentyl Ph- 8-(N)-N'-dimethylpiperazinium, I' ' 62 n-pentyl Ph- 8-NH-CBZ

63 n-pentyl Ph- 8-NHC(0)CgHll 64 n-pentyl Ph- 8-NHC(0)CH2Br 65- n-pentyl Ph- 8-NH-C(NH)NH2 66 n-pentyl Ph- 8-(2)-thiophene 67 n-pentyl Ph- 9-~ethyl 68 n-pentyl Ph- 9-ethyl 69 n-pentyl Ph- 9-iso-propyl 70 n-gentyl Ph- 9-tent-butyl 7I n-pencyl Ph- 9-Of:

72 n-pentyl Ph- 9-OCH3 73 n-pentyl Ph- 9-0(iso-gropyl) 74 n-pentyl Ph- 9-SCH3 75 n-pencyl Ph- 9-SCCH3 76 n-pentyl Ph- 9-SC2CH3 77 n-pentyl Ph- 9-SCH2CH3 78 n-pentyl Ph- 9-NH2 79 n-pentyl Ph- 9-NHOH

80 n-pentyl Ph- 9-NHCH3 81 n-pentyl Ph- 9-N(CH3)2 82 n-pentyl Ph- 9-N+ (CH3) 3, I

83 n-pentyl Ph- 9-NHC(-O)CH3 84 n-pentyl Ph- 9-N(CH2CH3)2 85 n-pentyl Ph- 9-NMeCH2C02H

86 n-gentyl Ph- 9-N'(Me)~CH2C02H, I' 87 n-pentyl Ph- 9-(N)-morpholine 88 n-pentyl Ph- 9-(N)-azetidine 8g n-pentyl Ph- 9-(N)-N-methylazetidinium, I' 90 n-pentyl Ph- 9-(N)-pyrrolidine .

9I n-pentyl Ph- 9-IN)-N-methyl-pyrrolidinium, I' 92 n-pentyl Ph- 9-(N)-N-methyl-morpholinium, I' g3 n-pentyl Ph- 9-(N)-N'-methylpiperazine g3 n-pentyl Ph- g-(N)-N'-dimethylpiperazinium, I' WO 98/x0375 PCT/US98/03792 95 n-pentyl Ph- 9-NH-CSZ

96 n-pentyl Ph- 9-NHC(O)CgHIl 97 n-pentyl 8h- 9-NHC(O)CH2Hr 98 n-pentyl Ph- 9-NH-C(NH)NH2 99 n-pentyl Ph- 9-(2)-thiophene I00 n-pentyl ph- 7-OCH3, 8-OCH3 101 n-pentyl ph- 7-SCH3, 8-CCH3 102 n-pentyl Ph- 7-SCH3, 8-SCH3 103 n_Dentvl Ph- 6-OCH3, 7-OCH3, 8-OCH3 Pret3~c . Cpd~ R1~R2 (FFF . x~oc . vw) F101.004 0I ~ n-hexyl Ph- 7-methyl 02 n-hexyl Ph- 7-ethyl 03 n-hexyl Ph- 7-iso-propyl 04 n-hexyl Ph- 7-te_~-butyl OS n-hexyl Ph- 7-OH

06 n-hexyl Ph- 7-OCH3 07 n-hexyl Ph- 7-Ofiao-prooyl)~

. 08 n-hexyl P:1- 7-SC:?3 09. n-hexyl Ph- 7-SOCH3 IO n-hexyl Ph- 7-S02CH3 I1 n-hexyl Ph- 7-SCH2CH3 I2 n-hexyl ph_ ~-N1,2 13 n-hexyl Ph- 7-NHOH

14 n-hexyl Ph- 7-NHCH3 15 a-hexyl Ph- 7-N(CH3)2 16 n-hexyl Ph- 7_N+(CH3) I-I7 n-hexyl Ph- 3, 7-NHC(~0)CH3 18 n-hexyl Ph- 7-N(CHZCH3)2 19 n-hexyl Ph- 7-NMeCHZC02H

20 n-hexyl Ph- 7-N+(Me)ZCH2C02H, I-21 n-hexyl Ph- 7-(N)-morpholine 22 n-hexyl Ph- 7-(N)-azetidine 23 n-hexyl Ph- 7-(N)-N-methylazetidinium I' 24 n-hexyl Ph- , 7-(N)-pyrrolidine 25 n-hexyl Ph- 7-(N)-N-methyl-pyrroliainium I' 26 n-hexyl Ph- , 7-(N)-N-methyl-morpholiniuta I' 27 n-hexyl Ph- , 7-(N)-N'-methylpiperazine 28 n-hexyl Ph- 7-(N)-N'-dimethylpiperazinium I' 29 n-hexyl Ph- , 30 n-hexyl Ph- 7-NHC(O)CgHll $5 31 n-hexyl ph- 7-NHC(O)CH28r 32 n-hexyl ph- 7-NH-C(NH)NH2 33 n-hexyi ph- 7-(2)-thiophene 34 n-hexyl Ph- 8-methyl 35 n-hexyl Ph- 8-ethyl 36 n-hexyl Ph- 8-iso-propyl 37 n-hexyl Ph- 8-tert-butyl 38 n-hexyl Ph- 8-OH

39 n-hexyl ph- 8-OCH3 40 n-hexyl ph- 8-0(iso-propyl) 41 n-hexyl Ph- 8-SCH3 .42 n-hexyl Ph- 8-SOCH3 43 n-hexyl Ph- 8-S02CH3 -44 n-hexyl Ph- 8-SCH2CH3 45 n-hexyl Ph- 8-NH2 46 n-hexyl Ph- 8-Ne:OH

47 n-hexyl Ph- 8-NHC:?3 48 n-hexyl Ph- 8-N(CH3)2 4 n-hexyl p!~- 8 +~
9 -N. (CH3) 3, I' ..

50 n-hexy l Ph- 8-NHC(=O)CH3 51 n-he:cyl Ph- 8-N (CH2CH3) 2 52 n-hexyl Ph- 8-NMeC::2CO2H

53 n-hexyl Ph- g-N+(;~e)2CH2C02H, I-54 n-hexyl Ph- 8-(N)-morpholine 55 n-hexyl Ph- 8-(N)-azetidine 56 n-hexyl Ph- 8-(N)-N-methylazetidiniuni, I-57 n-hexyl Ph- 8-(N)-pyrrolidine 58 n-hexyi Ph- 8-(N)-N-methyl-pyrrolidiniurl, I' 59 n-hexyl Ph- 8-(N)-N-methyl-morpholiniur~, I' 60 n-hexyl Ph- 8-(N)-N'-methylpiperazine 61 n-hexyl Ph- 8-(N)-N'-dimethylpiperazinium, I-62 n-hexyl Ph- 8-NH-CeZ

63 n-hexyl ph- ~ 8-NHC(0)C5H11 64 n-hexyl Ph- 8-NHC(0)CH28r 65 n-hexyl Ph- 8-NH-C(NH)NH2 66 n-hexyl Ph- 8-(2)-thiophene 67 n-hexyl Ph- 9 -methyl 68 n-hexyl Ph- 9-ethyl 69 n-hexyl Ph- 9-iso-propyl 70 n-hexyl ph- 9-tert-butyl 71 n-hexyl Ph- 9-OH

72 n-hexyl Ph- 9-OCH3 4- ~

73 n-hexyl Ph- 9-O(iso-propyl) 74 n-hexyl Ph- 9-SCH3 ~

_ 75 n-hexyl Ph- 9-SOCH3 76 n-hexyl Ph- 9-S02CH3 77 n-hexyl Ph- 9-SCH2CH3 - 78 n-hexyl Ph- 9-NH2 7g n-hexyl Ph- 9-NHOH

80 n-hexyl Ph- 9-NHCH3 81 n-hexyi Ph- 9-N(CH3)2 82 n-hexyl Ph- 9-N~(CH3) 3.
83 n-hexyl Ph- g-NHC(-O)CH3 _ 84 n-hexyl Ph- 9-N(CH2CH3)2 85 _ a-hexyl Ph- 9-N.!eCH2C0yH

86 n-hexyl Ph- g-N*(Me)2CH2COZH, Z' 8? n-hexyl Ph- g-(N)-morpholine 88 n-hexyl Ph- 9-(N)-azetidine 89 n-hexyl Ph- g-(N)-N--ethylazetidiniura I-90 n-hexyl Ph- , 9-(N)-py.=olidine 9I n-hexyl Ph- g- (;y) -N-methyl-py;=olidinit:~s I' 92 n-hexyl Ph- , g- ~~t -N-r..ethyl-morpholiniu -93 n-hexyl Ph- .~~, I
g-(N)-N~-methylpiperazine 93 n-hexyl Ph- g-(N)-N~-di.Tethylpiperaziniu ~
I-95 n-hexyl Ph- .
, 9-Ni:-C32 96 n-hexyl Ph- 9-NrC(0)CgHll 97 n-hexyl Ph- g-NHC (0) C::28r 98 n-hexyl Ph- 9-N::-C (N ) NH2 99 n-hexyl Ph- 9-(2)-thiophene 100 n-hexyl Ph- 7-OCv3, 8-OCH3 101 n-hexyl Ph- 7-SCH3, 8-OCH3 102 n-hexyl Ph- 7-SCH3, 8-SCH3 103 n-hexvl Ph- 6-OCH3, 7-CCH3, 8-OCH3 8refix Cpd$ R1=g2 fFfF.za. ) F101.005 O1 iso-propyl Ph- '7-methyl 02 iso-propyl Ph- 7-ethyl 03 iso-propyl Ph- 7-iso-propyl 04 iso-propyl Ph- 7-tert-butyl 05 iso-propyl Ph- 7-OFI

06 iso-propyl Ph- 7-OCH3 07 iso-propyl Ph- 7-O(iao-propyl) 08 iso-propyl Ph- 7-SCH3 09 iso-propyl Ph- 7-SOCH3 iso-propyl Ph- 7-502CH3 il iso-propyl Ph- 7-SCH2CH3 I2 iso-propyl Ph- 7-NH2 13 iso-propyl Ph- 7-NHOH

14 iso-propyl Ph- 7-NHCH3 iso-propyl Ph- 7-N(CH3)2 16 iso-propyl Ph- 7-N+(CH3)3, Z

17 iso-propyl Ph- 7-NHC(~O)CH3 18 iso-propyl Ph- 7-N(CH2CH3)2 19 iso-propyl Ph- 7-NMeCH2C02H

iso-propyl Ph- 7-N*(Me)ZCH2C02H, Z' 21 iso-propyl Ph- 7-(N)-morpholine 22~ iso-propyl Ph- 7-(N)-azetidine 23 iso-propyl Ph- 7-(N)-N-aethylazetidiniu.-1, I-24 iso-propyl Ph- 7-(N)-pyrrolidine iso-propyl Ph- 7-(N)-N-methyl-pyrrolidinium, I' 26 iso-propyl Ph- 7-(N)-N-ethyl-marpholiniu.~.i, I-27 iso-propyl Ph- 7,(Nl-N'-~:ethylpiperazine 28 iso-propyl Ph- 7-*N7 -.1' -dimethylpipezaziniu.~a, I' 29 iso-propyl Ph- 7-NH-C3Z

iso-propyl Ph- 7-NEC (0) C5~:11 31 iso-propyl Ph- 7-Ni:C (O) CHZBr 32 iso-propyl Ph- 7-NiT.-C (N:i) NH2 33 iso-propyl Ph- 7-(2) -t::iophene 34 iso-propyl Ph- 8-methyl iso-propyl Ph- 8-ethyl 36 iso-propyl Ph- 8-iso-propyl 37 iso-propyl Ph- 8-tent-butyl 38 iso-propyl Ph- 8-OH

39 iso-propyl Ph- 8-0CH3 iso-propyl Ph- ~ 8-0(iso-propyl) 41 iso-propyl Ph- B-SCH3 42 iso-propyl Ph- 8-SOCH3 43 iso-propyl Ph- 8-S02CH3 44 iso-propyl Ph- 8-SCH2CH3 iso-propyl .Ph- 8-NH2 46 iso-propyl Ph- 8-NHOH

4? iso-propyl Ph- 8-NHCH3 48 iso-propyl Ph- 8-N(CH3)2 49 iso-propyl Ph- 8-N+(CH3)3, I' iso-propyl Ph- 8-NHC(-O)CH3 5i iso-propyl Ph- 8-N(CH2CH3)2 52 iso-propyl Ph- 8-NMeCH2C02H

53 iso-propyl Ph- 8-N'(Me)=CH2C02H, I-54 iso-propyl Ph- 8-(N)-morpholine 55 iso-propyl Ph- 8-(N)-azetidine - 56 iso-propyl Ph- 8-(N)-N-methylazetidinium I-57 iso-propyl Ph- , 8-(N)-pyrrolidine 58 iso-propyl Ph- e-(N)-N-methyl-pyrrolidinium I-59 iso-propyl Ph- , 8-(N)-N-methyl-morpholinium I-60 iso-propyl Ph- , 8-(N)-N'-methylpiperazine 61 iso-propyl Ph- 8-(N)-N'-dimethylpiperazinium, I' 62 iso-propyl Ph- 8-NH-CBZ

63 iso-propyl Ph- 8-NHC(0)C5H11 64 iso-propyl Ph- 8-NHC(0)CH28r 65 iso-propyl Ph- 8-NH-C(NH)NH2 66 iso-propyl Ph- 8-(2)-thiophene 67 iso-propyl Ph- 9-methyl 68 iso-propyl Ph- 9-ethyl 69 iso-propyl Ph- 9-is o'-propyl 70 iso-propyl Ph- _ 9-tert-butyl 71 iso-propyl Ph- 9-OH

72 iso-propyl Ph- 9-OCH3 73 iso-propyl Ph- 9-O(iso-propyl) 74 iso-propyl Ph- 9-SCH3 75 iso-propyl Ph- 9-SOCH3 76 iso-propyl Ph- 9-502CH3 77 iso-propyl Ph- 9-SCH2CH3 78 iso-propyl Ph- 9-NH2 79 iso-propyl Ph- 9-NHOH

80 iso-propyl Ph- 9-NHCH3 81 iso-propyl Ph- 9-N(CH3)2 82 iso-propyl Ph- g-N+(CH3)3, I-83 iso-propyl Ph- 9-NHC(-O)CH3 84 iso-pzopyl Ph- 9-N(CH2CH3)2 85 iso-propyl Ph- 9-NMeCH2C02H

86 iso-propyl Ph- 9-N'(Me)1CH2C02H, I-87 iso-propyl Ph- 9- (N) -rnorpholine 88 iso-propyl Ph- 9-(N)-azetidine 89 iso-propyl Ph- 9-tN)-N-methylazetidinium I' 90 iso-propyl Ph- , 9-tN)-pyrrolidine 91 iso-propyl Ph- g-tN)-N-methyl-pyrrolidinium, I-92 iso-propyl Ph- g-(N)-N-methyl-morpholinium, I-93 iso-propyl Ph- 9-(N)-N'-methylpiperazine 93 iso-propyl ph- 9-(N)-N'-diraethylp$iaiu -95 iso-propyl ph- m, I

96 iso-propyl ph- 9-NHC(0)C5H11 97 iso-propyl Ph- 9-NHC (O) C'rI2Br 98 iso-propyl Ph- 9-NH-CiNH)NH2 99 iso-propyl Ph- 9-f2)-thiopheae 100 iso-propyl Ph- 7-OCH3, 8-OCH3 101 iso-propyl ph- 7-SCH3, 8-OCH3 102 iso-propyl ph- 7-SCH3, 8-SCH3 103 iso-nroDVl Ph- 6-OCH3, 7-OCH3, 8-OCH3 8ret3s Cpd; R1=R2 R5 x (R
(F'F'F . s~oc ) q . ) F181. 00 6 iso-butyl Ph- 7-methyl Ol 02 iso-butyl Ph- 7-ethyl 03 iso-butyl Ph- 7-iso-propyl 04 iso-butyl Ph- 7-tent-butyl 05 iso-butyl Ph- 7-0L

06 iso-butyl P::- 7-0CL3 .

07 iso-butyl Ph- 7-0(iso-propyl) 08 iso-butyl Ph- 7-SC33 Og iso-butyl Ph- 7-SOCa3 iso-butyl Ph- 7-502CH3 Il iso-butyl Pr.- 7-SCi~2Cag 12 iso-butyl p:~_ 7-NH2 13 iso-butyl Pr- 7-NHOH

14 iso-butyl Ph- 7-NHCH3 iso-butyl Ph- 7-N(CH3)2 16 iso-butyl Ph- 7-N+fCH
-17 iso-butyl Ph- 3)3. I

NHC(-O)CH3 i8 iso-butyl Ph- 7-N(CHZCH3)2 19 iso-butyl ph- 7-NMeCH2C02H

iso-butyl Ph- 7-N'(Me)=CH2C02H, I-21 iso-butyl Ph- 7-(N)-morpholfne 22 iso-butyl Ph- 7-(N)-azetidine 23 iso-butyl Ph- 7-fN)-N-methylazetidiai -24 iso-butyl Ph- tua, I
7-(N)-pyrrolidine iso-butyl Ph- 7-(N)-N-methyl-pyrrolidini -26 iso-butyl Ph- um, I
7-(N)-N-methyl-morpholiniu I-27 iso-butyl ph- ia, 7-(N)-N'-methylpiperazine 28 iso-butyl ph- 7-(N)-N'-dimethylpiperaziaium I-29 iso-butyl ph- , 30 iso-butyl ph- 7-NHC(0)CSHii -31 iso-butyl ph- 7-NHCIO)CH2Br 32 iso-butyl Ph- 7-NH-C(NH)NH2 33 iso-butyl Ph- 7-(2)-thiophene 34 iso-butyl ph- 8-methyl 35 iso-butyl ph- 8-ethyl 36 iso-butyl Ph- 8-iso-propyl 37 iso-butyl Ph- 8-tert-butyl ~ a ~,~yl ;P~~~ -8-Ai~-39 iso-butyl ph- 8-OCH3 40 iso-butyl ph- 8-O(iso-propyl) - 41 iso-butyl Ph- 8-SCH3 42 . iso-butyl ph- 8-SOCH3 43 iso-butyl Ph- 8-S02CH3 44 iso-butyl Ph- 8-SC::2CH3 45 iso-butyl Ph- 8-NH2 46 iso-butyl ph- 8-N'r'.OH

47 iso-butyl Ph- 8-NHCH3 48 iso-butyl ph- 8=N (C~i3 ) 2 49 iso-butyl ph_ 8-N+(CH3)3. I- ..

50 iso-butyl ph- 8-NFC(-0)CH3 51 iso-butyl Ph- 8-N(CH2Ci3)2 52 iso-butyl Ph- 8-NMec~:2co2H

53 iso-butyl Ph- 8-N'(Me)=CH2C02H, I-54 iso-butyl Ph- 8-(N)-corpho line 55 iso-butyl Ph- 8-(N)-azetidine 56 iso-butyl Ph- 8-(N)-N-methylazetidinium, I-57 iso-butyl Ph- 8-(N)-pyrrolidine 58 iso-butyl Ph- 8-(N)-N-methyl-pyrrolidinium, I-59 iso-butyl Ph- 8-(N)-N-methyl-morpholiniu~, I' 60 iso-butyl Ph- 8-(N)-N'-methylpiperazine 61 iso-butyl Ph- 8- (N) -N'-dirscthylpiperaziniuas, I-62 iso-butyl ph- -NH-CBZ

63 iso-butyl ph- 8-NHC(0)CgHil 64 iso-butyl ph- B-NHC(0)CH28r 65 iso-butyl ph- 8-NH-C(NH)NH2 66 iso-butyl Ph- 8-(2)-thiophene 67 iso-butyl Ph- 9-methyl 68 iso-butyl ph- 9-ethyl 69 isv-butyl Ph- 9-iso-propyl 70 iso-butyl Ph- 9-tort-butyl 71 iso-butyl Ph- 9-OH

72 iso-butyl Ph- 9-OCH3 73 iso-butyl Ph- 9-O(iso-propyl) 74 iso-butyl Ph- 9-SCH3 75 iso-butyl Ph- 9-SOCH3 76 iso-butyl Ph- 9-502CH3 ?7 iso-butyl Ph- 9-SCH2CH3 78 iso-butyl Ph- 9-NH2 ' 79 iso-butyl Ph- 9-NHOH

80 iso-butyl Ph- 9-NHCH3 81 iso-butyl ph- 9-N(CH3)2 82 iso-butyl Ph- g-N+(CH3)3, I' 83 iso-butyl Ph- 9-NHC(-0)CH3 84 iso-butyl Ph- 9-N(CH2CH3)2 85 iso-butyl Ph- 9-NMeCH2C02H

86 iso-butyl Ph- g-Ni(Ne)ZCH2C02H, I-87 iso-butyl Ph- 9-(N)-r..orpholine 88 iso-butyl Ph- 9-(N)-azetidine 89 iso-butyl Ph- g-(N)-N-"tethylazetidiniu.-.1, I' 90 iso-butyl Ph- g-(PL) -pyrrolidine 91 iso-butyl ph- g~' -~EN) -N-methyl-pyrrolidiniu.~a, I' 92 iso-butyl Ph- g-(N)-V-methyl-morpholiniu.-n, I' 93 iso-butyl Ph- 9-(N)-N'-r..ethylpiperazine 93 iso-butyl Ph- g-(N)-N'-di.~ethylpiperazinium, I' 95 iso-butyl Ph- g-NF:-G5Z

96 iso-butyl Ph- g-Ni:C (0) C5~T11 97 iso-butyl Ph- g-NFiC (0) CH2Hs 98 iso-butyl P::- 9-NE-C (NF:) NH2 99 iso-butyl Ph- 9-(2)-thiophene 100 iso-butyl Ph- 7-OCV3, 8-CCH3 101 iso-butyl Ph- 7-SCH3, 8-OCH3 102 iso-butyl ph- 7-SCH3, 8-SCH3 103 iso-butyl Ph- 6-OCH3, 7-OCH3, 8-OCH3 pretis Cpd~ R1=R2 RS (R=) Q
_I~'~'S' . ~oo~
. 5~y1 F10 1.007 O1 iso-pentyl Ph- 7-methyl ~

02 iso-pentyl ph- 7-ethyl 03 iso-pentyl Ph- 7-iso-propyl 04 iso-pentyl ph- 7-tent-butyl OS iso-pentyl Ph- 7-OH

06 iso-gentyl ph- 7-OCH3 07 iso-pentyl Ph- 7-0(iso-propyl) WO 98/40375 PCT/tJS98/03792 08 iso-pentyl Ph- 7-SCH3 09 iao-pentyl ph- ?-SOCH3 isa-pentyl ph- 7-S02CH3 11 iso-pentyl ph- 7-SCHZCH3 12 iao-pentyl ph- 7-NH2 - 13 iso-pentyl ph- 7-NHOH

14 iso-pentyl ph- 7-NHCH3 iso-pentyl ph- 7-N(CH3)2 16 _-_iso-pentyl Ph- 7-ri~(.CH3.?~,-I- _ 17 iso-pentyl ph- 7-NHC(~O)CH3 18 iso-pentyl Ph- 7-N(CH2CH3)2 19 iso-pentyl Ph- 7-N.!eCH2C02H

20- iso-pentyl Ph- 7-N'(Me)=CH2C02H, I-21 iso-pentyl Ph- 7- (N) -:.-.orpholine 22 iao-pentyl Ph- 7-(N)-azetidine 23 iso-pentyl Ph- 7- (N) -N-r:ethylazetidiniurn, I-24 iso-pentyl ph- 7-(N)-pyrrolidine iso-pentyl P::- 7-(N)-N-methyl-pyrrolidiniu.-t I' 26 iso-pentyl Ph- , 7- (N) -N-met::yl-. :rorpholiniu.-1, I-27 iao-pentyl Ph- ?-(:4r-N'-r..ethylpiperazine 28 isa-pentyl Ph- 7- (N) -N'-d=.~ethvlpiperaziniu.~.i, I-29 iso-pentyl Ph- 7-Nri-C3Z

iso-pentyl Ph- 7-NHC(O)C5~11 31 i~o-pentyl Ph- 7-NEC(0)CHZHr 32 iso-pentyl Ph- 7-Ns-C(NH)N:i2 33 iso-pentyl Ph- 7-(2)-thiophene 34 iso-pentyl Ph- 8-r.,ethyl iso-pentyl Ph- 8-ethyl 36 iso-pentyl Ph- 8-iso-propyl 37 iso-pentyl Ph- 8-ter;.-butyl 38 iso-pentyl Ph- 8-OH

39 iso-pentyl Ph- 8-OCH3 iso-pentyl Ph- 8-O(iso-propyl) 41 iso-pentyl ph- 8-SCH3 42 iao-pentyl Ph- 8-SOCH3 43 iso-pentyl ph- 8-S02CH3 44 iso-pentyl Ph- 8-SCH2CH3 iso-pentyl Ph- 8-NH2 46 iso-pentyl Ph- 8-NHOH

47 iso-pentyl Ph- 8-NHCH3 48 iso-pentyl Ph- 8-N(CH3)2 49 iso-pentyl ph- 8-N+(CH3) 3, I-50 iso-pentyl Ph- 8-NHC(-O)CH3 51 iso-pentyl Ph- 8-N(CH2Cx3)2 52 iso-pentyl Ph- 8-NMeCH2C02H

53 iso-pentyl Ph- 8-N'(Me)=CH2C02H, I' 54 iso-pentyl Ph- 8-(N)-morpholine 55 iso-pentyl Ph- 8-(N)-azetidine 56 iso-pentyl Ph- 8-(N)-N-methylazetidinium I' 57 iso-pentyl Ph- , 8-(N)-pyrrolidine 58 iso-pentyl Ph- 8-(N)-N-methyl-p,~rrolidinium,-I-- ~-$~ s =pentyl Ph- 8-(N)-N-methyl-morpholinium I' 60 iso-pentyl Ph- , 8-(N)-N'-methylpiperazine 61 iso-pentyl Ph- 8-(N)-N'-dimethylpiperaziniurs I' 62 iso-pentyl Ph- , 8-Nx-C8Z

63 iso-pentyl Ph- 8-NHC(0)CgHll .

64 iso-pentyl Ph- 8-NHC(0)CH29r 65 iso-pentyl Ph- 8-N::-C (NH) NH2 66 iso-pentyl Ph- 8-(2)-thiophene 67 iso-pentyl Ph- 9--Methyl 68 iso-pentyl Ph- 9-e~hyl 69 iso-pentyl Ph- 9-iso-propyl 70 iso = 9-tent-butyl pentyl Ph-71 iso-pentyl Ph- g-OH

72 3so-pentyl Ph- 9-OCH3 73 iso-pentyl Ph- 9-0(isa-propyl) 74 iso-pentyl Ph- 9-SCx3 75 iso-pentyl Ph- g-SOCH3 76 iso-pentyl Ph- 9-S02CH3 77 iso-pentyl Ph- 9-SCH2CH3 78 iso-pentyl Ph- 9-NH2 79 iso-pentyl Ph- 9-NHOH

80 iso-pentyl Ph- 9-NHCH3 81 iso-pentyl Ph- 9-N(CH3)2 82 iso-pentyl Ph- 9-N+(CH3)3 I-83 iso-pentyl Ph- .
9-NHC(-0)CH3 84 iso-pentyl Ph- 9-N(CHZCH3)2 85 iso-pentyl Ph- 9-NMeCH2C02H

86 iso-pentyl Ph- 9-N'(Me)2CHZC02H, I' 87 iso-pentyl Ph- 9-(N)-morpholine 88 iso-pentyl Ph- 9-(N)-azetidine 8 9 iso-pentyl Ph- 9- (N) -N-~thylazetidinium I' 90 iso-pentyl Ph- , _ 9-(N)-pyrrolidine 91 iso-pentyl Ph- g-(N)-N-methyl-pyrrolidinium, I' 92 iso-pentyl Ph- g-(N)-N-methyl-morpholinium I' , ~J ~' 93 iso-pentyl Ph- 9-(N)-N'-methylpie 93 iso-pentyl Ph- g_(N)_N'-dimethylpiperazini -95 iso-pentyl Ph-. um, I

96 iso-pentyl Ph- 9-NHC(C)C;HlI

97 iso-pentyl Ph- 9-NHC(C)CH28r 98 iso-pentyl Ph- 9-NH-C(NH)NH2 99 iso-pentyl Ph- 9-(2)-thiophene IO_0 _ iso-pentyl Ph- 7_OCx~B~CH_~
_ ~

101 iso-pentyl Ph- 7-SCH3, 8-CCH3 102 iso-pentyl Ph- 7-SCH3, 8-SCH3 I03 iso-oeatvl Ph- 6-OCH3, ?-OCH3, 8-OCH3 8re~iz Cpd~ R1~R2 RS (Rx) ' ' q F
F.me. wy) _(F

r 101. 008 OI CHZC (=O) C=H;Ph- ?-methyl 02 CH=Ct-OJCZHS Ph- ?-ethyl 03 CH2C(-0)C=H; Ph- ?-iso-prooyl 04 CHIC(=0)CIH; Ph- ?-pert-butyl ' os cH2c (-o) c2H;ph_ ?~,.

os cHZC t-o) c2x;Ph- ?-acJ3 07 CHIC(-0)C2H; Ph- ?-O(iso-psopyl) 08 CHZC(-O)CZH; Ph- ?-SCH3 09 CH2C (-0) C=H;ph- 7-SCCH3 IO CH=C (=O) CZH;Ph- ?-S02Ci?3 Il cH2c(=o)c=H; Ph- ?-scH2cH3 I2 CH2C(=O)CZHS Ph- ?-NH2 13 CsZC(=o)CZH; Ph- ?-NHOH

14 CHIC (=O) C2H;Ph- 7-NHCH3 IS CHIC(=O)CZHS Ph- ?-N(CH3)2 16 cxZc(=o)c=H; Ph- ?-N+tcH3) I-17 cH=c (=o) czHSPh- 3, 7-NHC (=o) cH3 18 CH2C (-O) C=H;Ph- 7-N (CH2CH3) 2 19 CHIC(-O)C=H5 ph- 7-NMeCH2C02H

20 CHIC (=O) CZH;Ph- 7-Na (~!e) 2CH2C02H, I' 21 CHZC(-O)C=Hg Ph- 7-(N)-morpholine 22 CHIC(-O)CIHS Ph- 7-(N)-azetidine 23 CH2C(-O)CIHS Ph- 7-(N)-N-caethylazetidinium, I-24 CHIC(=O)CZHS Ph- 7-(N)-pyrrolidine 25 CH=C(-O)CIHS Ph- ?-(N)_N-methyl-pyrrolid3nium I' 26 CHZC(-O)C=HS Ph- , 7-(N)-N-methyl-morpholiniurn, I' 27 CHIC (=O) CZH;Ph- 7- (N) -N' -ctethylpiperazine 28 CH2C(-O)CIHS Ph- 7-(N)-N'-d~ethylpiperazinium, I-29 CHIC(-O)CZHs Ph- 7-NH-C3Z

30 CH=C(-O)C=HS Ph- 7-NHC(0)C5H11 31 CHIC(-O)CZHg Ph- 7-NHC{0)CH2Br 32 CHIC(-O)C=HS Ph- 7-NH-C{NH)NH2 33 CH=C (-O) C=Hg ph- 7- (2 ) -thiophene 34 CH=C(D)C=Hg Ph- 8-methyl 35 CH2C(-O)C=Hg ph- 8-ethyl 3 6 CHZC(-O)CZHS ph- 8-ino-propyl_ 37 CHI C 8-tcrt-butyl (=O)C=Hg Ph-38 cHZC(=o)C=HS Ph- 8-off _ 39 CHIC(-O)C=H5 Ph- 8-OCH3 40 CHIC(=O)CZHS Ph- 8-a{iao-propyl) 41 CH=C(-O)C=H3 h- 8-SCH3 P

42 CHIC(=O)C=HS Ph- 8-SOCH3 43 CvZC{=O)CZHg Ph- 8-so2cx3 44 C'c:ZC (=O) Ph- 8-SCH2CH3 ClHg 45 C:?ZC (=O) C2 Ph- 8-NH2 46 CH=C {-O) C2H5 ph- 8-IJHOH

47 CiiZC (-O) CZH;Ph- 8=~~t'r,:CH3 48 C:iZC (-O) C=H5Ph- 8-:1 (Cag) Z

49 CHyC{=O)C=HS Ph- g-N+(Cs3) I' 50 CH=C (=O) C=HS Ph- 3, 8-Ni:C (=O) CH3 51 CHZC(-O)C=Hs Ph- 8-N(CHZCH3)2 52 CHIC (=0) C2H; Ph- 8 :'~1:!eC::ZC02H

53 CHIC{-O)CZHS Ph- 8-N'(Ne)=CH2C02H, I-54 CH=C(-O)C=Hg Ph- 8-{N)-morpholine 55 CHIC(=O)CZH3 Ph- 8-(N)-azetidine 56 Ci:~C (=O) C1H5Ph- 8- {N) -N-methylazetidinium I' 57 Cli=C (=0) C=HgPh- , 8- {N) -pyr rolidine 58 CH=C{=O)CZHg Ph- 8-(N)-N-methyl-pyrrolidinium, I-59 CHZC(-0)CZHg Ph- 8-(N)-N-methyl-morpholinium, I-60 CHIC(=O)C=H3 Ph- 8-(N)-N~-methylpiperazine 61 CHIC {=O) C=Hg Ph- 8- (N) -N' -dimethylpiperazinitua, I' 62 CHIC(=O)CZHB Ph- 8-NH-C8Z

63 CH=C(=O)C=Hg Ph- 8-NHC(O)C5H11 64 CHIC{=0)CZHS Ph- 8-NHC(0)CHZer 65 CHIC (=0) CZHS ' Ph- 8-NH-C {NH) NH2 66 CHIC (-O) CZHS Ph- 8- (2) -thiophene 67 CH=C(=O)C=HS Ph- 9-methyl 58 CH=C(=C)CZHS Ph- 9-ethyl 69 CHZC(-O)CIHS Ph- 9-iso-propyl ~6 ?0 cH~c(=O)C=HS ph- 9-tert-butyl 71 cH=c(-o)czHS Ph- 9-off 72 CH=C(-O)CZHS ph- 9-OCH3 ?3 CHIC(-O)CZHj ph- 9-O(iso-propyl) ?4 CH=C(=O)CZH~ ph- 9-SCH3 75 CHIC(-O)CZH3 Ph- 9-SOCH3 ? 6 CHIC (=O) CZHg Ph- 9-502CH3 ?7 cHic(=o)ciHS ph- 9-5cH2cH3 78 CH=c (-oI C=HS ph-?9~ __-CH=C (=0.).CZi,F~__gh_ -~NHOH-_ 80 cHZC(-o)c2H5 ph- g-NHCH3 81 CHIC(=O)CZHS Ph- 9-N(CH3)2 82 CHIC(-0)C=H3 Ph- 9-N+(CH

3)3, 83 CHIC(=0)C=H5 ph- 9-N

HC(=O)CH3 84 cHZc(=o)cZHS Ph- 9-N(cH2cH3)Z

85 cHZc (=o) cZHS Ph- g .~rr:ecH2CO2x 86 CHIC(=0)CIHq Ph- 9-N'(Me)~Ca2C02H, I-87 CH2C (=O) CZH3 ph- 9- (N) -..~aorpholine 88 CHIC(=O)CZHg Ph- g-fR)-azetidine 89 CH2C (=O) C2H5 Ph- 9- ~~~ :.N-r.,ethylaietidiniur -90 CH=C(=O)CZHS Ph- i, I
9-(N)-py_rolidine . 91 CH2C (-0) C=H5 Ph- 9- (N) -N-aethyl-PYrrolidini -92 CH=C (=0) CIH; Ph- ura, I
g- (N) -N-methyl-mo~holiai I-93 CHIC(=O)C=H~ Ph- u~, 9-(N)-N'-methylpigerazine 93 CHIC (=0) C=H: ph- g-(N) -N-dy~ethylpiperaziniu -95 cxZC(=o)c2H~ Ph- ri, I
9-NH-Caz 96 CHIC(=0)C=H5 Ph- 9-NHC(0)C5HI1 97 CHIC (=0) CZ Ph- g-N::C (0) CHZar Hg g8 CHIC (=0) CzHS Ph- 9-NH-C (NH) NH2 cH~c (=0) CZ ph- g- (2 ) -thiophene HS

100 CH=C(=0)CZHS ph- 7-OCH3, 8-OCH3 i01 cHzc(=o)czHS Ph- ~-5cH3, 8-ocH3 102 CHIC(=O)C=HS Ph- 7-5CH3, 8-5CH3 103 cHlc (-o) c ph- s-ccH3, ~-ccH3, e-ocH3 Hs Cpd# RhR2 R5 ~

~R
~ q FIOI

. CHIOC1H5 Ph- 7-methyl 02 cH2oc=HS Ph- 7-ethyl 03 cH~ocZHS ph- 7-iso-propyl .

04 CHIOCZHS ph- ?-tert-butyl J~

05 CH=OCIxs Ph- 7-off 06 CH=OC=H5 Ph- 7-ocH3 07 CHZOC~Hg Ph- 7-O(iso-propyl) 08 CHZOCZHS Ph- 7-SCH3 09 CHZOCZHS Ph- 7-SOCH3 to cH~ac=Hg Ph- 7-S02CH3 11 cHZ0cIH5 Ph- 7-5cH2CH3 12 CHZOCZHS Ph- 7-NH2 _-I3 CHZOCZHg Ph- 7-NHOH

14 CH=OC=HS Ph- 7-N'riCH3 15 CH~OC=HS Ph- 7-N(CH3)2 16 CH2oczH5 Ph- 7-N+(cH3)3, __ 17 cHZOC=H5 Ph- 7-NHC(-o)cH3 .

18 CHIOCZHS Ph- 7-N(CH2CH3)2 is CHZOCZHS Ph- 7-N:feCH2C02H

20 CHZOCIHS Ph- 7-N* (We) ZC:i2C02H, I-21 CHZOCZHg Ph- 7-(N)-morpholine 22 CH20CIH5 Ph- 7-(N)-azeti~.i.ne 23 CHZOCZHS Ph- 7- (~1) =N-methylazetidiniu.~a, I' 24 CH=OCZH3 Ph- 7-(N)-pyrrolidine 25 CHZOCIHS Ph- 7-(N)-N-methyl-PYrrolidinit:.~n, I' 26 C~i=OCIHS Ph- 7-(N)-N-methyl-morpholiniu.~n, I' 27 CHIOCZHg Ph- 7-(N)-N'-~ethylpiperazine 28 CH=OCZHS Ph- 7- (N) -N -~~ethylpiperazini~~a, I' 29 CHZOC=H5 Ph- 7-NH-C3Z

30 CF:=OCZHS Ph- 7-NHC(0)CgHlI

31 Ca20C~Hg Ph- ?-NHC(0)CH23r 32 Ca~OCZHS Ph- 7-NH-C(NH)NH2 33 CHZOCZH3 Ph- 7-(2)-thiophene 34 CHZOCZHS Ph- 8-methyl 35 CH=OC=Hg Ph- 8-ethyl .

36 CH=0C=HS Ph- 8-iso-propyl 37 CHZOC~HS Ph- 8-tert-butyl 38 CH=OCZHS Ph- 8-OH

39 CHZOCZHg Ph- 8-OCH3 .

40 Cx~oCZHS Ph- 8-O(iso-propyl) 41 CH20C=H5 Ph- 8-SCH3 42 CH~OC2Hg ph- 8-SOCHg 43 CH=OCZHS Ph- 8-502CH3 44 CHZOC=HS Ph- 8-SCH2CH3 45 CHIOC=Hg Ph- 8-N~t2 46 CH=OC=Hg Ph- 8-NHOH

47 CHZOC~HS ph- 8-NHCH3 48 CHZOC=HS ph- 8-N(CH3)2 49 CHZOC=HS Ph- 8-Nf(CH3)3, I-50 CH=OCZHS Ph- 8-NHC(-O)CH3 51 CH=OC=HS ph- 8-N(CH2CH3)2 52 cH2ocZHS ph- e-NMecH2co2H

53 CH=OC=HS Ph- 8-N'(Me)~CHZC02H, I-54 CH~OCIHS ph- 8-(N)-aorpholine 55 CH=OCIHg Ph- 8-(N)-azetidine _ _ 56 CH=OCZHS __ _ _ Ph- 8-(N)-N-methylazetidinium I-57 CH20CZH5 ph- , 8-(N)-pyrrolid.ine 58 CHZOCZHS ph- 8-(N)-N-r..ethyl-pyrrolidiniuca I-59 CH=OC2H5 Ph- , 8-(N)-N-saethyl-morpholiniuia, I-60 - CHZOC=HS Ph- 8-(N)-N'-methylpiperazine 61 CH2OCIH5 Ph- 8-(N)-N'-dimethylpperaziniu.-a, Z-62 CHZOCZHS Ph- 8-NH-C3Z

63 CH=OCZHS ph- 8-N:~C (O) C5H11 64 CHZOC2H5 Ph- a-NHC (0) C::ZBr 65 CH=OC2H5 Ph- 8-NL'-C (N ) NeI2 66 CH20CZH5 Ph- 8-(2)--thioohene 67 CH20C2H5 Ph- 9-s:ethvl 68 C.T-IZOC2Hg P::- 9-ethyl 69 CHIOC=H5 Ph- 9-iso-propyl 70 CH20CZHg Ph- 9-tent-bLLyl 71 CHZOCZHS Ph- 9-OH

72 CH=OCZHS Ph- 9-OCj3 73 CH20C=HS Ph- 9-0(iso-propyl) 74 CHZOCZHS Ph- 9-SCHg 75 CHZOCZHg Ph- 9-SOCH3 76 CH=OC=HS Ph- 9-so2cH3 77 CHIOCZHS Ph- 9-SCH2CH3 78 CHZOC=HS Ph- 9-NHZ

79 CHZOC=H5 ph- 9-NHOH

80 CHZOC=HS Ph- 9-NHCH3 81 CH=OCZHg Ph- 9-N(CH3)2 82 CH=OC2Hg Ph- 9-N+(CH3)3, I-- B3 CH20C=HS ph- 9-NHC(0)CH3 84 cHZOCZHS ph- 9-N(cH2cH3)2 85 . CH=OC=HS ph- 9-NMeCH2C02H

86 CH=OC=HS ph- 9-N' (Me) =CH2C02H, I- .

87 CHIOCZHS Ph- 9-(N)-morpholine Sg 88 cHSOC=H; Ph- 9-(N)-azetidine 89 CHIOCZHS Ph- g-(N)-N-r..ethylazetidinium, I' 90 CH~OCZHg Ph- 9-(N)-pyrrolidine 91 CHZOCZHS Ph- 9-(N)-N-aethyl-pyrrolidiniura, I-92 CH~OCZHS Ph- 9-(N)-N-methyl-morpholiniurs, Z-93 CHIOC=H; Ph- 9-(N)-N'-methylpiperazine 93 CH=OCZH; Ph- g-(N)-N'-dimethylpiperazinium, I' 95 CHIOC=H; Ph- 9-NH-CBZ

_~g~.... _.Cx=OCZHS _.P.h_ ..9-NHC-(OrCgiill _ 97 cHiociH; Ph- 9-NHC(o)cH2sr 98 cH~oc=Hs Ph- 9-NH-C(NH)NH2 ' 99 CH20CyH; Ph- 9-(2)-thiophene 100 CH20C1H; Ph- 7-OCHg, 8-OCH3 101 CH~OC=H; Ph- 7-SCH3, 8-0CH3 i02 CHZOC2H; Ph- 7-SCH3, 8-SCH3 103 CH20CZH5 Ph- 6-0C::3, 7-OCH3, 8-OCH3 Pre=is Cpd'~ R1.R2 RS (R=~~ .

_SF'~'.sa.
wv) FIO 1. 0 IO C'ZCa (OH) C2H;Ph- 7-:.~,ethyl 02 CHZCH(OH)CZH; Ph- 7-ethyl 03 CH=CH(OH)C=H; Ph- 7-iso-propyl 04 CHlCa(OH)CZH; Pa- 7-tent-butyl 05 CHZCH(OH)C=H; Ph- 7-OH

06 CH=CH (OH) C=H;Ph- 7-OCF:3 07 C:iICH (OH) Ph- 7-0 (i3o-propyl) CIH;

08 CVZCH(OH)CZH; Ph- 7-SCH3 09 CH=CH(OH)CZH; Ph- 7-SOCH3 CHZCH (OH) CZH;Ph- 7-S02CF:3 11 CH~CH(OH)C=H; Ph- 7-SCH2CH3 12 CHZCH(OH)CZH; Ph- 7-NH2 13 CH=CH(OH)CZH; Ph- 7-NHOH

14 CHICH(OH)CZHS Ph- 7-NHCH3 CH=CH(OH)C=H; Ph- 7-N(CH3)2 i6 cH~cx tax) ciHSPh- ~-N+ (cH3 ) 3, I-17 CHZCH(OH)CZH; Ph- ~-NHC(-o)cH3 18 CH=CH(OH)C~HS Ph- 7-N(cH2cH3)2 19 CHZCH(OH)C=HS Ph- 7-NMeCHzC02H

CH=CH(OH)C2H5 Ph- 7-N'(Me)~cH2CO2H, I-21 CH=CH(OH)CZH; Ph- 7-(N)-morpholine 22 cHZCx(oH)c=HS Ph- 7-(N)-azetidine d 23 CH=CH (OH) CZHS8h- 7- (N) -N-rethylaze~un, 24 CH=CH(OH)CIHS Bh- 7-(N)-pyrrolidine 25 CH=CH(OH)C=HS Ph- 7-(N)-N-methyl-pyrrolidiaium, I' - 26 CHICH(OH)C=HS Ph- 7-(N)-N-methyl-morpholiniu.-n, I-27 CHZCH(OH)C=HS Ph- 7-(N)-N'-methylpiperaziae _ 28 CHZCH (OH) C=HgPh- ?- (N) -N' -ditnethylpiperaziniu.~n, I' 29 CH2CH (OH) C=H5Ph- 7-Nii-CHz 30 CHICH (OH) C=HsPh- 7-NFiC (0) CSHll 31 CH2CH(OH)C=Hg Ph- 7-NHC(0)CH2Hr ~~_.- _ --CHiCH ___Ph_-7=NH-C-(NH) NF~2 -(OH)~CzHS _.._ _ -.33 CH=CH (OH) CyHSPh- 7- (2) -thiophene 34 CHZCH(OH)CZHS Ph- 8-methyl 35 - CH=CH(OH)C=HS Ph- 8-ethyl 36 CH=CH(OH)CZHS Ph- 8-iso-propyl 37 CHZC:i(OH)C=H3 Ph- 8-ter:-butyl 38 cxzc~:(OH)C=H3 Ph- 8-off 39 GH2C:i (OH) Ph- 8-OC3g CZHS

40 C::ZC.'-'.(OH)CZHSPh- 9-fl.(~so-propyl) 41 G:?=CH (OH) Ph- 8-Si.:i3 C=H3 42 cH=G::(oH)czs~ Ph- 8-sacx3 43 C::ICa (OH) Ph- 8-S02C:i3 C=H5 44 C:i2C (OH) CZHSPh- 8-SCHZC:i3 45 CHZC::(OH)CZH~ Ph- B-NH2 46 CH2CH(OH)CZHS Ph- 8-NHOH

47 CH=C::(OH)C=H~ Ph- 8-NHCH3 48 CuZCa(OH)CZH3 Ph- 8-N(GH3)2 49 CJZCi: (OH) Ph- 8-N'~' (Cii3) 3, I-C=H3 50 C::ZC:( (OH) Ph- 8-NF~C (~0) CH3 51 C::=C:: (OH) Ph- 8-N (CH2CH3) 2 CZHS

52 CF:=CH (OH) Ph- 8-NMeCii2C02H
C~HS

53 CH=CH(OH)C=Hg Ph- 8-N'(Me)ICHZC02H, I-54 CH2CH(OH)CZHS Ph- 8-(N)-morpholine 55 CHICH(OH)C1H5 Ph- 8-(N)-azetidine 56 CHZCH(OH)CZHS Ph- 8-(N)-N-methylazetidiniuas, I-57 CHICH(OH)CIHS Ph- 8-(N)-pyrrolidiae 58 CH=CH(OH)C=HS Ph- 8-(N)-N-methyl-pyrrolidinium, I' 59 CH2CH (OH) CIHSPh- 8- (N) -N-methyl-saorpholini~,ua, I-60 CHZCH(OH)CZHS ph- 8-(N)-N'-methylpiperaziae 61 CHiCH(OH)C=HS Ph- 8-(N)-N'-dimethylpiperazinium, I-- 62 cx2cH(oH)C=HS Ph- a-NH-CHz 63 CHZCHiOH)CIHg Ph- 8-NHC(0)C5H11 64 CH=CH(OH)C=HS Ph- 8-NHC(0)CH2Hr 65 CH=CH(OH)C=H; ph- 8-NH-C(NH)NH2 66 CH=CH(OH)C=HS Ph- 8-(2)-thiophene 67 , CHZCH(OH)CZHSph- 9-methyl 68 CHZCH(OH)CIH; ph- 9-ethyl 69 CHICH(OH)C=H; ph- 9-iso-propyl 70 CH=CH(OH)CIH; Ph- 9-tent-butyl 71 CH=CH(OH)C=H; ph- g-OH

72 _._ __ ~x2cH ph- _g-__ac~3____ c_ox) cix;

73 CH2CH(OH)C=H5 Ph- 9-0(iso-propyl) 74 CH=CH(OH)CZHS Ph- 9-SCH3 75 CHZCH(OH)CIH; Ph- 9-sOCH3 76 CHICH (OH) CZHSPh- 9-sO2CH3 77 CH~CH(OH)C2H3 Ph- 9-sCH2CH3 78 CHZCH (OH) C2H5Ph- 9-NH2 79 CsZCH (OH) CZH;Ph- 9-NHOH

80 CH2CH (OH) C2H;Ph- 9-NHCi3 81 CF:ICT. (OH) Ph- 9-N (C::3) 2 CZH;

82 C'.-:ZCH (oH) ph- g-N(C,3) 3, r Cih;

83 CH2CH (OH) CI::;Ph- 9-Nc~.'C'(-O) CH3 ..

84 CvZC~ (OH) C= Ph- 9-N (CsZCu3) Z
;

85 Cz=C:: (Ox) Ph- 9-~1:~!eC.'-2COZH
CZc;

86 Cs2CH (OH) CZeT.~Ph- 9-Nf (Me) =Cs2C02F:, I-87 C::ZCH (OH) Ph- 9-!N) -morpholine C=Fr;

88 CHZCH (OH) CZi~;Ph- 9- (N) -azetidine 89 CH=CH (OH) CZr;Ph- 9-!N) -N-methylazetidiaii..m, I-90 Cs2C: (OH) CZi!;Ph- g- (N) -pyrrolidine 91 CHZCHlOH)CZH; Ph- g-(N)-N-methyl-pyrrolidinium, Z-92 CHZCF! (OH) Ph- g-(N) -N-methyl-morpholinium, CIF:; Z-93 CHZCH (OH) CZH;Ph- 9- (N) -N~ -methylpiperazine 93 CH=CH(OH)C=H; Ph- 9-(N)-N'-dimethylpiperazinium, I-95 CHZCH(oH)CZH; Ph- g-NH-CaZ
.

96 CHZCH(OH)CZH: Ph- 9-NHC(O)CgHll 97 CH~CH(oH)CZHS Ph- 9-NHC(0)CH29r 98 CHICH(OH)CZH; ph- 9-NH-C(NH)NH2 99 CH=CH(OH)ClHg ph- 9-(2)-thiophene I00 CH=CH(OH)CIH; P h- 7-OCH3, 8-OCH3 ioi cH2cx(oH)c=H; ph- 7-scH3, 8-ccH3 102 CHICH(OH)C=H5 Ph- 7-SCH3, 8-SCH3 103 CHZCH(oH)cZHS Ph- 6-OCH3, 7-OCH3, 8-OCH3 Bret3s Cpd~ R1~R2 Rs (Rx) Q
(FF'F . r~ . YYY) F101.011 01 CHZO-(4-picoline)ph- 7-methyl 02 CH20-(4-picoline)Ph- 7-ethyl 03 CH10-(4-picoline)ph- 7-iso-propyl 04 CH=O-(4-picoline)Ph- 7-tent-butyl OS CH=0-(4-picoline)ph- 7-OH

06 CHZO-(4-picoline)ph- '7-OCH3 , -QT- -CHZO= C4-picTine)_.ph-?-O ( so-propyl) 08 CH=0-(4-picoline)Ph- 7-SCH3 09 CH=0-(4-picoline)Ph- 7-SOCH3 ~i0 CHZO-(4-picoline)Ph- 7-S02CH3 11 . CHZO-(4-picoline)Ph- 7-SCH2CH3 12 CH10-(4-picaline)ph- 7-Nv2 13 CH20-(4-picoline)Ph- 7-NHOH

14 CH20- ( 4-picoline)Ph- 7-Ni:CH3 15 CHZO-(4-picoline)Ph- 7-N(CH3)2 16 CHZO- ( 4-picoline)Ph- 7-~t (~H3 ) 3 .

17 CHID- I4-picoline)Ph- 7-.~fie (-O) CH3 ..

18 CHZO-(4-picoline)Ph- 7-N(CH2Cs3)2 19 CH20- ( 4-picoline)Ph- ?-N.:eC~:2C02H

20 CHzO- ( 4-picoline)Ph- 7-N' (::e) ~C::2C02H, I-21 CHID- (4-picoline)P::- 7- (N) -morpholine 22 CHZO-(4-picoline)Ph- ?-(N)-azetidiae 23 CHZO-(4-picoline)Ph- 7-(N)-N-Tethylazetidinium, I-24 CHZO-(4-picoline)ph- 7-(N)-pyrrolidine 25 CH=0-(4-picoline)Ph- 7-(N)-N-methyl-pyrrolidiniu.-z, I' 26 CH20-(4-picoline)Ph- 7-(N)-N-methyl-morpholinium, I-27 CHZO-(4-picoline)ph- 7-(N)-N'-methylpiperazine Z8 CH10- ( 4-picoline)Ph- 7- (N) -N' -dir.:ethylpiperazinima, I' 29 CH~O-(4-pieoline)Ph- 7-NH-CSZ

30 CH10-(4-picoline)Ph- 7-NHC(O)CgHll 31 CH=O-(4-picoline)Ph- 7-NHC(O)CH28r 32 CH=O-(4-picoline)Ph- 7-NH-C(NH)NH2 33 CH=O-(4-picoline)Ph- 7-(2)-thiophene 34 CHZO-(4-picoliae)Ph- 8-methyl 35 CH=O-(4-picoline)Ph- 8-ethyl 36 CHZO-(4-picoline)Ph- 8-iso-propyl - 37 CHZO-(4-picoline)Ph- 8-tent-butyl 38 CHZO-(4-picoline)Ph- 8-OH

39 CH=O-(4-picoline)Ph- 8-OCH3 ~3 40 CH=O-(4-picoline)Ph- 8=0(iao-propyl) 41 CHZO-(4-picoline)Ph- 8-SCH3 42 CH10-(4-picoline)Ph- 8-SOCH3 43 CH=O-(4-picoline)Ph- 8-S02CH3 44 CHZO-I4-picoline)Ph- 8-SCH2CH3 45 CH20-(4-picoline)Ph- 8-NHZ

46 CHZO-(4-picoline)Ph- 8-NHOH

47 CH=O-(4-picoline)Ph- 8-NECH3 48 CHZO-(4-picoline)Ph- 8-N(CH3)2 49 CH=O-(4-picoline)Ph- g-N+;CH3)3, I-50 CH=0-(4-picoline)Ph- 8-NHC(-O)CH3 51 CHZO- ( 4-picoline)Ph- 8-N (CH2C:13 ) 2 52 CH=O-(4-picoline)Ph- 8-NMeCH2CO2H
.

53 CH20-(4-picoline)Ph- 8-N'(Me)2CH2C02H, I-54 CHZO- ( 4-picoline)Ph- g- (N) -no ~holine 55 CHZO-(4-picoline)Ph- 8-(N)-azetidine 56 CH=O-(4-picoline)Ph- g-(N)-N-~ethylazetidinium, I-57 CH20-(4-picoline)Ph- 8-(N)-py==olidine 58 CH=O-(4-picoline)Ph- 8-EN)-N-methyl-pyrroiidiniura, I-._ .
;

59 CHZO-(4-picoline)Ph- .
, g-(N)-N-methyl-morpholinium, I' 60 CH10-(4-picoline)Ph- g-(N)-N'-~ethylpiperazine 61 CHZO-(4-picoline)Ph- g-(N)-N'-dir.ethylpiperaziniun, I' 62 CH20-(4-picoline)Ph- 8-N:i-C3Z

63 CH~O-(4-picoline)Ph- 8-NHC(O)C5H11 64 CHZO-(4-picoline)Ph- 8-NHC(0)CH2Hr 65 CH=O-(4-picoline)Ph- 8-NH-C(Nr)NH2 66 CHyO-(4-picoline)Ph- 8-(2)-thiophene 67 CHZO-(4-picoline)Ph- 9-crethyl 68 CHZO-(4-picoline)Ph- 9-ethyl 69 CHZO-(4-picoline)Ph- 9-iso-propyl _ 70 CHID-(4-picoline)Ph- 9-tert-butyl 71 CH=O-(4-picoline)ph- g-OH

72 CH20-(4-picoline)Ph- 9-OCH3 73 OHIO-(4-picoline)Ph- 9-O(iso-propyl) 74 CH=O-(4-picoline)Ph- 9-SCH3 75 cH~o-(4-picoiine)Ph- 9-socH3~

76 CHZO-(4-picoline)Ph- 9-SO2CH3 77 CH=O-(4-picoline)Ph- 9-SCH2CH3 78 CH=O-(4-picoline)Ph- 9-NH2 . .
.

79 CH=O-(4-picoline)Ph- 9-NHpH

80 CHZO-(4-picoline)Ph- 9-NHCH3 81 CH=O-(4-picoline)Ph- 9-N(CH3)2 82 CH=O-(4-picoline)ph- 9-N+(CH3)3. _-83 cH=o-(4-picoiins)Ph- 9-NHC(-o)cH3 84 CH~o-(4-picoline)Ph- 9-N(CH2CH3)2 85 CHZO-(4-picoifne)Ph- 9-NMeCH2C02H

86 CHZO-(4-picoiine)Ph- 9-N'(Me)ZCH2CO2H, Z' 87 CHZO-(4-picoline)Ph- 9-(N)-morpholine 88 CH~O-(4-picoline)ph- 9-(N)-azetidine 89 CHZO- (4-picoline)Ph- 9- (N) -N-methylazetidiniuin _-- 90- CHZO-(4-pico-l-ine-)--Ph-_., . ..9--(N)wpyrro3idine-_ _..
__ 91 CHZO-(4-picoline)Ph- 9-(N)-N-methyl-pyrrolidinium I' 92 CHZO-(4-picoline)Ph- , 9-(N)-N-methyl-morpholiniur.~
Z' 93 CHZO-(4-picoline)Ph- , 9-(N)-N'-methylpiperazine 93 CHZO-(4-picoline)Ph- 9-(N)-N'-dimethylpiperazini~a, ~ I' 95 CH20-(4-picoline)ph- 9-NH-C3Z

96 CHZO-(4-picoline)Ph- 9-NHC(O)C5H11 97 CHIO- (4-picoline)Ph- 9-N::C (O) C::28r 98 CH=O-(4-picoline)Ph- 9-NH-C(N::)NH2 99 CH=O-(4-picoline)Ph- 9-(2)-thiophene 100 CHZO-(4-picoline)Ph- 7-OCF3, 8-OCH3 101 CHIO-(4-picoline)Ph- 7-SCH3, 8-OC:a3 I02 CJ20-(4-picoline)Ph- 7-SC3, 8-SCH3 I03 CH20-(S-picoline)ph- 6-OC::3, 7-OC::3, 8-CCa3 vv ;

'~ o~ , ~

oa .. .

o cEc ~ a of ~~E -~ -Q o 0Ca ~a CE CC C

EE~ -~ ~'= ~E _ t~ ~ f s E

EEZ ~~ ~x av a ~

a raC E vv rirs r LYn CC ~i ' t~
--.-__ T.T._ __ y C

C

C

N
C

L

n v v c 4J v ~

C

G ~ ~' y v r vv 'L xv x v ~ _ = = 7 v v Z

a V

cr G

- _ _ _ _ =r y= =

S

r r C C y C CC y= CC

_ - _ - . ..

yi L_ i 3 . _~ ~- __ 7 t _~=

C

w _ 2E ~ o 'a o o~ oc~ ~ ~

G

OZ

U

L, w PA
~o d~-.. ~ e~~ c c o .. o c c _ 0 0 o c s. y p ~ 'n x ~Y x ir. v .~. - x x a o E o o a ~ y ~ o =
z o ao y oo ao ~_ eyu' = E s _ ri ~ - v v V 0 d t ~ y ~ r ~ C
° ~ ~ ~a ~ ~ ~e : ~ v Z ri f~
4 IC !C 4 r C C
n n __ _ -_ v x- x r v 2 i Z
I ~ rs I
c -v v v v v v _y L _ x ~ x d ~ O. ,. v c - a _ a ~ :!
C
n T. ~O T = .1. O
0 ~ ~ ~ 0 ~ 0 t S
y ~ ;~ ~ ' '..~ a '~
C C C C C C C C C c I
I
s ' t ~'' s_ _ ~ s 7.
~ v a V C C C y v v v v N ~ ~ N f'' a' N P'1 N1 ~ !9 l~~f ~ C~'I N

6~

WO 98!40375 PCT/US98/03792 P

o o ~ ~ a C '~ x O fl x ~~ Q 0 x Xv =' = r =_'3~ = C
s = Q ss ~ ~ ~ ~c ~ '~ x x ov ~ ~c ~ ~ s ~
v ~ v s Q ..' o ri~ o s~ y w'~'~= -o r - c E v v ~ ~ ~ ~ ~ ~ ~ ."-.E c' p c c~ s 'c n E E ri:.ewtv ' .. ..y ~s :rsrr.., ~ y , F ~ ~ ~ = ~,. cv ~~'-cscsr ~ y E
. A ' ~ ~ E r: ~;
ew n C _ e: '~
~ _ 'a a ~ n, cv ' E
O

c _ _ ,~_ 8 _ Z Z a Z s;.
.~ o~ - Z c c s c S .i iT.C c .i.2 =S ZZ Z Z
~ yc s s C vZ L ~ ~ "_ a ~
c a L

_- ~ s _y _~ y y :!J .! :7 .7 L C) = L .._ _ y Z x x ~= .. x . - - . _ = Z _ _ O
v v ~ ~ T ~' C ~v : ~ y ' N JL _ 1 ' L L
= v v 1 L
L

h e~f ~ ~ ~ ~ ~ P9N e;NT

_ O = O = O Z Z O = y _=
O O = i 0 0 00 O O= = G 0 0 0 0 O 000 000 0 _ _ ~. ~ _ _ _ ~, C _ > > ~ 7 ~ ~ Z 3 _ _ yE _ __ C C
C C C ~ C C ? ~ 7 C C C C y C C C_ C C .~. C C C C C C
C C C C

i , ~' _ _ _ it ~ a as s v ~ - _ 'u _ a v y~ 7 ~r ~
v s w v ~ i y 7 .~ 7 Z
y y v o~ w L c a.a ~
~ 'u v s s c E c z a m~ 0~.'~~ ~ C11 C.~~G~1 N N ~ ~ N N N N N N ~ N NN N N~ N
N N N N N N N N
N

6'l PA1~
c c °c ' ' a c =
~E E ~E ~ '= c c a r. G a a r y a, iv a E E E y E
v, ~ '~~ ''?
n Z
U O
+ Z ~ U -+ _ Z= Zs +
O O
,G Z
O = _ O
O
8 + ~, 8 + ~, a f a y y O O ~ O

7 7 7 ~ 3 C C C C C ? C
?v iv iv iv i, .
v 3~ ~ y v v c n ,., o C C = C C
.s .s E s .s .rs a. a. a. = a, a.
a E '~_ E ~ E
Wv q ~ _ n Z
/ \ o /
O V
+ v ° Z v ~ +~-_ +z ~ ~ z i . n U /O J 2~ \
N
O +\x ., ti U ~O
O O ~ O
Z Z
O O O O O O
_a' r. a, a, C C a C C
a' av a, a.
c = c c c c .. ° a~
° ° ° ~ 0 0 ..
~i a °c ° c ' E E a E =
s a es ~e r:
a. = a. a. a.
E E E E E
n n ~ , v O
v +Z
Z ~ O + \ +~ +
Z ~ Z e.~ Z n O ~ O . s.
O O O
O
2' 3.' $' 3 > >
a c ~ c a~ a, a. a.
' ~ > >
a c a c a..
a .. .. ..

c a c c c c' .E ~w .a E ~ .c av a r.
s ~'' ~. a.
v ... . s E C c E v v ' ~ ~ C
tv n. cy . :Q
A
Z
Z
= V
O N
U_ Z Z -~. C
f N/ \Z f Z ~ V ~ Z~ ~'z + ~ ~ n N
~ ~~
~ O ~~ ~ O
_ O ~'r / s O
O O
Z t O
O
> ; °'' ~ a, c c c =.
a, 'a.
.° ~ .s . 3 c c p C
O

c a c c ' ' c =
~E E E E ~E E
s a _a ~ a r a. a. a, s E E E a E E
n ~ ~ n n Z
w n O
!1 U N N
= V _U
't t2 ~Z t~
O ~ +/ ~ i . . ~ ''' z ~ U
~' w x _" v\
O " ~ O
s s 3 N
Z T=
Z

i, a, _a, > >
c c c a c a, a. - _a. - a.
C G C C C C
o ~ ~ ~o ~6 _ c ° ~ ~ °c a ~
_s R ~ E E 'c c es rs r ~' i~ _ ?v ~ a, r v v v E E E 'e ;~ ;o ;o .
. Z
N
S U
Z- ~ V = U V
tZ U ,O U Z
t ~ n t Z m ~w C Z
O t ..
a U U~
O ZZ ti O o .: ti O '~ ,., O ~ _ Z Z

=' ~' ~ ~. a. - a, a a c a , i~
c a a i, a. a, a. a. . a, ..
c 3 ~ ~ ~ ~ ~
' ~ c c c a a a ~e ~~ ~E E
a a a a a, a. av a, a.
v v d i' a E E E E
v vo v \ ~ \
V +
+ z Z °' O
.
C
. ~., +z _, z O u. O ~ '~ u. O
_ O
T '_' T

_a, a, ~_. a, _a, C C C C
z a. a, a~ a. a, C C C G
O
O ~ ~ ..

PA

a c ' ~ c R
av a, n Z
z' Z Z z~.
f +
'" + 2 Z
\ +~ / ~ \ Z ~
G -Hi ~ z ~ ~ ~ +~~
x "' z . U~ ~ - ~
O ..
O
O
O
O
T
C C C 'R
C
C
G C
C C
_ A
O
'~ 9 c o c o 0 0 .'c_ c _c c c rs ~E E ~E E
° rs a rs y y a' ~. a, C v v v v E~ E E
n Z z / \ /
J \/ p p Z \
N
C

O G
v - / n G O _ ..'.
p e%~ p O
T_ G G O 0 ' .D ~ = 3 C C C
C

V C .a C C
7f C1 ~ ~' N
'ufJ O O ~ ~ O

'- c c y 'E c c a, a, a, .~ .~.
y y = ~ ~, ..
a E ~ " y - z ~ ?_ E '° yq n Z
U
N
-F UN ~ i.
Z U i-.t. 2 Z n O .'-a O O O
t O
O . O.
. a, _ a.
c C G C
a, 7 : ~~ ~ iv ~ 7 C C
C C C
'. ~.

C C C C ~ L C
E E E E 'c 'E E ~_ a a a a a ~~ a s i. a, - j~ ~ av E E E_ n n ' ' n~e~'.n t?'w Z Z
Z U
v 2 e~~ t ~ ~ ~ O ~ t /~ ~ a, -'' ~ y t ' O
ti O a 3 "
ti O _ ~
O
O
Z Z Z
O O O O O
a. a, ~. ~ a, _a, .a ~ ~ ~ .~
a a a C c a. a. _a, _a. .- a. _a. >

~w O O ~ O d c a e_e a c c E E E ~E E E
a ~~ ~ ss~
a, a, - ;" ,, - a, a E E E E ~ v v 'v~? ~, ~;cy' Z
/ \
~ + ~j- - o /~ _ Z t ~2 v _ +
+ Z
C
Z i"~ x m r.
~ C
v x Z+ ~ y o _ O= G
O ~e O
O
\ /
=s - __ a ~, - ~, ,, s ~~~
m o00 _..

c c ~R _~17 _~rJ _~R
v v n a n x =
\ C -o o 0 _ , , T_ 7 ~ r -° .a c a.
a, c a c ..

a c c a c c c °c c ~E E ~E -E ~E E E E
s ~ s s ~ R s ~
a, a, a, ~ -. ~, - a.
a v v v a a v y v ' c E E E E E E E
'Q . , :Q :Q :o ~ :Q ' x x x U
V U
w tZ Z t2 t t -v ' eh v v ~ ~ e~ _ ~ 'Z t O er x %
-vv O . O E E ~ p 3 p s x x a, ~ a, a, ' a, a, z ~ z a ~
~a a c c c c c c c a, a, a, - ;, - a, > >
~a C C C y G c c c ~. ~' ~go r ~ c c c ~ _ ~ o ~E R ~m s _s a ~ ~E
"__ s s .~ '~ ~ a, ~ v a d y y y ~ E E E E
:Q ;o :~
~ cw ~ ~ . '°
' Z Z
O
O
t 2 ~L
v + 2 r~. t ti O x ~ o -. ~ = 2 W
.~ e~~ O t' -:~

C O
G O
Z== Z Z
S
O 0000 p=O O
_..
--7 ~ ~ 7 C C C C C C C C
_ 7 ~~ T _ ~ ~
c c c v v v c C C
~°
.-~~ ~ ~", N
~ w~.~ , ,~

c a c °e °e a °c E E E E - _ _ R a R R R 8 E~'e ~ E E
R R f! R Q 11 IC Q
a y E E E E E E E = E E , a, ~ :a :g :o - E E
ew is ' is a ~ is ' ri Z
Z
x f U
z U O
Z
O
_ f y - . + ,~. v _ x 2 n - ~ Z .x. v v ~ Z _ x v ~'' ' '~
O a ~ ~ C
a v t ~ v O ~ o '=
v 'r a O O
ri ri r M
s" _ . .i =

O O
___ _ ~
"~a~ ~a a c c c a c c C a c a c -- ~ --~ _ - ;, - a, ~ s ~ ~ s 3 =_ C C C C C C C ~ C C
N
_-~ N ~ ~ ~ ~ a ~ N
~ ~~~ n~.~

- I
n o a c ~o G
0 ~ ~ rs a a E c ~ ~L~° _ _ ~ ~ 3 0 ~ ~ ~ .. o c E ~ E = _- _ _- c _ E ~ a E E E E ~= -c ~ = ~ .E ~ E
a a s a a - s rs rs a e: ~ - rs - a. a. __ a. a, a, rs ~ c = - r y v ~ y y ~ y y _ ' s = = ;, - _ a t EE FE BEEc y EE= "~_=c,yE,'.
d ~ ~ ~ ~s~ ~ ' ~,~=~ C

e~ ~ n ~ n y ew x H ' y ri J
L
~ 1 i !1 L = .Z 1 1 ~y s 'E
x z '- U_ v t ~ Z - ~ y ' y x v t ~ r x C v ," H r, _ (~~ L v r = - a ~ v = ~ ~ ~ = _ ~
Q y . o ~ ~ L x ~c ~ - x ~ ~ ~ x ~
~~t~~_~..pt a - ~ v r s t er p v e~ ~ ~ e:f ~'-_ r ~,j en ~
e~
.i. .i Z i ~ .i "' 3b Oo 00 0 0 0 000000000 ~. - ~. ~, =, _ -3 33 ~_=~ ; _ _ ~a ~~.? ' _~
G C C C t C t C C C C C .~ ~ L C C
- - ~ - - - ~ a. a.
3 ~ ~ J ~ 3 7 3 3 ~ ~ Z ~ 7 7 3 7 3 C C C C C C C ~ C C C t C C t C 3 C t C
f~9 ~ ~ a ~ ~ a ~ ~ ~ ~ g T ~ tff N If1 ~ 1~f1 1.. 1~1 1~ ~ r. ~ ~. ~ ~ ~ ~ ~
9~

:vQ y a :

a~v C = oC ~ o z - o ~o oE

.cc E a E ~ ~ -_ c =o c _ E . t . .

x a . E E e' ~
.

p - sR , c ~ s x E~ 'E ' ~ = " -= ~ ~ ~. c ' - .
~

o , _= .-- .._.. ooa, o _ = - c ~ ~a ~ _- xo o y :_'~'_ .x xE
_~ - - -_- EE s :' ._ _ oc ~ .... - ~
~c.

-~ w yv' yy y" E E _~Es~ -a= s E- ~a , o a_ ~o Ee $a, ~~ E ~ E v v '-E c; "~ ? s E

~ E = =E ; c c = , E Ec 'c ,= c nv R E ~ E ri ~ = C' ' _ ~= y C - r_riritv.T v '~ n ~r n n ~ l W, S - ~ ~ _ ~ ~ .~.-n S :' .

c w tw E es ~ ,cew , n ~~ - ' _ _ ~ ~

v ~

c ~ E~
.' . .

. : .,:

. _ _. d Z ZZ T Z iT2 S.S Z I ZZ Z

Z.i ~T.Z s Zi ~

~ ~

~ x x ~ x ~

;. y -v= -x y v ~ - ~~ -y'c ~ a~. - -__ = - ~ =o = _~

y ' -=L V O ~ _ _= r=_ _ 3_c =v__v ~= y~ ~~ a.
' -- ~ = =

0 5 -'a ~'' ~ ~ L _i.- xx ~ ~._.~_ - xy ~. - -x C L y 7 r ~ , ~' C ~ C~ s ~r.C~ 'L x _ _ ~ 1 - p 'C ~ - ..~ ~ _ ~~ C s _ ...

. _ y v ~ ~ ~ y -~ =~ ~ =- '1 - 'E -~ y .J ~ a ri T ~ p ~ ' riP !'1'J E j T ~C ~N C' '1 ~

.
u n .

v .~ ~- N
~

a7 f T..T...~ T'~? .~li ' ~ T
= ' ~ .
1. iL
~ .

Z _ ~

- - ~ ~ ~ _ _ _ _ __ __ _ _ _ ---r . . ~ ~ ~ -..

C C y : C C~ ~ = C C C ?7 7 7 C _ C ~

C ~C C CC C ~C C CC CC C
~

- - _ _ _~ - ~ _ _ _ _ _ _ __ ~
_ _ ~ -~ _ .-.'7 7 7" 7 w ~ ~ ..~ ~ ~ ~ ~ 37 '' 3 ~7 3J
C C C c C CC G C C y y C C C

C C C ~ C G CC C
C ~ C C

C CC C CC

4~1 ~ q ~.'..~~..~ ~~ ~ ~ = ~ T ~ N T t~
~ N

- ... . ~ ~~ . _.A ~
...

..
a 5 E a °e a a a ~ ~ ;. s a 'Ea a.
>. . t o ' a, ~ y E E E ~
v E ' Z
;,. .,.
,,.
c v ~1 \/
N ~ SI H ~ =I
!~
U
" '- + z _ L ~ :I ~ S
a r 1~ ~ ~ o f 11 ..
O
sae O '''~ a00 a. ~ a.
__'-' z z a c " a a C a ~_ _a. a. _ a, - a.
c c c a c a c 1 ~ 1 ~ w~ ~..
w~

WO 98!40375 PCT/US98/03792 = O ~ L =
E

a r. .~ \
,_ _ _ y $ ~ 1 V ~- _ _ c y +Z y y o i, v Z a _ O ,.. ~ - - c s ' ~ ~E
z + ' ' C = x y x i. ~ x u'f a .~ : - v v .. C
E = _ r N

_ - _ _ _ = O =
O 00 O 00 ~Op OZ. OO
ti r _ _ ~ ~ _ ~ ~ 9 7 ~
~s C C C C C . C y it _ ~ 7 3 S 7 7 C C C G C C C C C w C C C C
N ~ ~ N N O
,., N N N N !Y N N N
't 3 C C C C _C 0 C C C C C C C
o.E~ E ~~ E __ .'c E E.c. .E ~.c ~ a. a, 'rs E ~E ' = E -' o _rs r s o = _'a a vs L ~L a ' _' ~? _~s~ = _ s' ~ v .O y v v y~o E~ ~~ yoo E E L~ E
ri n 'p Gv [~ ~ ~ n _ = Z
a Z

U

- y v y = y = j =_= -'~ U"~ =_:_~ ~ v x x x O x -- y ~ 's c O ~ U ? y t _ ._ ~ a = = '~ /Z +
e~ Wn ~ N 3 ~ e.i a, c%f e~ ~"~
Z =_ __ = O

- ~ _ _ ~ =, ~, ~ av ~' .~o~ ~ ~ 3 ' ' = ~ ~ s 3 C C C C ~ C ~ C C C ~ C C
C C
- ~ _ ~ ~ ~ ~ ~ ~ a ~ 7 C C C C C ~ ~ C ~ G C C C C C C
~ '1_' ~7 N N N N N N N N N N N N N
N ~ N ~ ~ N N N N N N
9ø

WO 98/40375 . PCT/US98/03792 x +i i ~ _ ~ N U a .. O - y '3e Z ez ~ Z
U ~ d v ~ U "' y t Z t Z
= y ~ + .- u. O E c ~ O
~ ti O x a \/~~~\/> ~/
'~ 5 .V C C C C C ~ C C G
a ~ a ,a E ,Ea a a s a, ~, a, ' ' ~ s _ 'a E E E ~ " °' "
E E E E E
.'°"o www ' ev ~ ri ev n =x x Z
O N
Z' _h _ O
V ~ t Z =
_ er y Z , ~ y U
V ~ ~. Z ., v . = V Z ~ Z
~ v ~ ~ 'w ..
r.
n1 e~
x xZ
x x -00 00 0 0 000 ~ o '' _ ~ ='' _a.
c c =a ' a,' 3~'' ' c c c c a c c . c c =' ~ ~ ~ W, s ~' ~ . ~ ~
c = c c a c c c c c a ' H H ~ a a ~ H ~
,N., N ~ N !V H

V
~_g~ i~~ g a s ~ ~ a_e~e a_e ,E, .L p ~' iy..
E Ea~'o E y.E ~ E ~c: o a ~~ a n e~'~d,' ~, ~ ~.
c y. v y tl Z
U ~ iI N Z H
+ Z A
v = v _ + Z " ,_ y~ y ~ ~~~~G O 2 O
z +~_. t ~ " ' ' y °' ' =~_~ ~ O

i~ ~~ - r r _ _ _i1 r 3 '~
a c c a a a c a a a c c av a. _a, c c a a ~' ~' s =~.~z ~ y a a c a a c c '~3H
.. ,~, 9'?

c °e °-_ ~_ °c o 0 a rEs a s ~ .~ ~E
r a~ ?. ~, v a v L y y -yo 'v F E E . E
.i y ~
U
.'.
+ Z V U V Z , a p .~. U
, - O U~Z~_U ~ C 2 + 2 e~s + a \
~, z v f .. a ti p ,O +
ti O = ~- O O
a s O
O
\ /
x xx = x x z y c c c c c a. - a, ~, ~ ~,, ~ ~ ~ _ c c c, N ~ N N

~g~ g ~ ' a, ~ o Q ~ .E E ~ o p ~ c ~ =' % ~ "
_ E ~' = Y a a, o v vE v " o '-oE"x_xx E v ~sov'a y ~ ~ E ~ ~ 9,0'x -i-- , . :r s ~ _ o. ~ ; ~ .r h a.
x~

i. ~ V S T
Es a N
n A
Z A
H
_U tZ
t1 ~
V
O ~ N _ ~ w v .c x ~ ~ O 1 ~ ~ 0 O ~ x $ v L $ v v O E e:Z E ~ O 3 _ a O
O O O ' O 0000 __ o ~3_-___-3 c c C C C C C C C C C
_ 33 3 ~ ~~ ~
_-_ ccec eee c Z ~~cc=""
.. ,~ ~'' S

., ~j ~ ~" ~" $
[ O~

---~o ~ ~ c .
x . + z., ~ E o '~ ° 5 o c ~ R w a a '° y .' a = o ap .~Cav. =' ae s E~ ~ E
;q ~
a ev ~ . ~ .
Z

2 ~ f v ZZ Z '-~
'w _~'~ ~ O n a v r v ' v s ~ 0 E a O / O
_' Z t v y y C C C C C C C
~' iv > > ~ ~ >
C C y ~ V C ~ ? . 3 C = . C
N
C'! Pf N ~ ~ ~ N
.~ ,.. ,.. ,n to3 C C C C C C
_ .a. .a .rs .a .a .a t s_ ~ a, E E v E E E
'Q ~o Z
o z N
_o ~ _ _ U
O = ~ u7 + ~O f Z
" O ~ Z ~- U
O '"
a ~d v Z+
.s ~ ~ ~. o a o ' _ u. o ', ° ~ ~ o z t z O -W
.',0 3 ~ z .a c c c c .
'' a. '' a. a, 3 3 s = c c a c ~ c N
P'1 l'N~ N ~ ~ of _~

a °c ~ o .e E c s . ~ R
'' a, a. a.
v s_ t E y L
E
t n z z~ z + a z ~ ~~ ~ ~ z~
z.~z +
s - :.
0 0 = o O
z Z
Z _ O
r.

__ c c c a, a, a. a, s a c ...
.o .- .. ;.:
( Og .~ c =° e° a E s E . a " E
'' ~ a.
s E E ~ a , , '.C~ ", O U Z O-0 o N~ o --PS + + N
z ~ ~ + _ ~z o _ ~ o 0 0 ' z c a c c a, a, '., a, i c c a c ~ 09 a c a ~E E
a a a a a, a, a. a, s v v v v E E E
n e~
Z
\+l~--' ~+~~~ i -Z
-- o o -\ / \ / \ /
\ /
y a ~ c c a z ' '~ c e~
c .. .-~10 c ~ ~ o 'E _c a R rs .E .E
a, a, a.
E
3 w x , x - /\ /\
\\ o \ o o= ~ o --~+
+ ~+
'~+ +
o _ °_ 0 0 0 \ ~ \ / \ /
x x 0 0 ~ ~ o.
' ? z c c a c ° ° c c n a c a c a c ~E ~E ~E E
rs rs rs rs ~E a a. ~. a. a. a, a, v v v v v ~ E E E E E
'r i ~ _ w i v i t U = U
Z N V t Z V Z
t t Z = t tm t Z
...
O
O
O _, ~ O
O .
Z Z t Z Z
O O O O O
a, a. =. a. a.
> > z > >
c c c c c a, a. a, _a. ~ ~, .~0~ ~ 3 = ~ ' c c c C ~ c e~~f ~"~ ~ ao r- ..

3 ~ o c c s a ' ,~e ~ a '' a. ~ a, E v E E E
t~ e~ , 'v _ ' Z
U
U
'- ,_ ' + ev O ,_ _ O _ O
1 v T
O
r .'3~ 3 ?
C C C
~_ .O
C C C C
t13 a ~ o ~ o w R R R R R
E E
' ~ , 'q x , ~ i ~Z/ \
_ \
v z/+ ~_ Z N Z +
_Z
, , , 0 , x x C
C C C
C
a. a' C C C C a _ -.
' ' ~ = a c a R ~E ~E
a ~ ~ a R
c a C v ;Q E
:yo i' ' x x U ~+ ~ U
+Z
Z- +~ U
+z o ' 0 0 zx x ~,' .a c c 's .o C c ' c c~

c C° °
°e a ~rs R R .R .R
~1 ~1 ~1 ~1 " E ~y ~ a ;v .E' .a E
t~
Z
x O
O-~-O
U
O
v '~' t Z
N
ti O
O
u. O
x x O
~' ~ i C C C C C
~1 C C C
1 _ ! !

WO 98/403?5 PCT/US98103?92 ° ~ a '° s av a, a, a.
s a E c ev ~ 'Q
z Z ~ t ~ ~ U
m Z +
N Z

o ~

a c c a a 3 ;
c c a c '' .. ..
1 I''1 C C C
s _R .E .E
_R fi S ~ ~ iv .a Z
a z \ + z' O
U
U ~ Z
t d.
,Z N
N
U - O ~s O
= u. O
ti O
Z
O
O
O
a a, a c a. a, .o .o c a a a .°.
a a n U
~Zf ~ ~ Z ~ + U
t' 2 .~2 t - a s a a a a z ~z i~q C C C
.a .R a .E
r s a E E E E
w 'Q :a o x _~
z '- i N
ti x 1 U
~i-?~
x ' \ U
u. O O- U
x a.
c a _a, ~, ~
C c a' a r, t~
a tao E E ° ~ c ~E
a, a, s R
a ~~
E .~~. y ~ =
w c E_ E
., _~ _ _ _ ,_ ~, .;
z z V _N
U
U
+Z
~Z
2~
+ +
. O
zx ~c' ~- ~ ~- n o a _ c x y x z s z ;c ' c ~ a c c a ~ z ~ s c ~ a, c c . c N
T q N !
! !
~, !
tai a c R '° a a a, a. a, a, a.
v y y y C E E E C
x N x +Z
_O n h -F Z
~c' V ' ..
C
O
x T

r ~ ~ _!~
> >
C C C
.7 'J . 7 t1 .O
C C C C
H
N
T

c °c ~ ~ a .,: .~ .R c E
a~ i~ R rs s ~ s y n O x O
II,O
Z N ~ +,~ '-'Z O ,- U
Z N Z C'1 O ~- O
O / ~ O . ~ O

z x T_ O O O
r _?v '.S1 .0 .7 C C = C
~_ r '.~ ~ > > .
C C C C ~ C
c1 l~~f t~3 WO 98!40375 PCT/US98/03792 c c a a c .s .R .E
s ~ s a, a, a, a, ~, a, s E E E c E c r s t _o ' ~ U

Z " Z
t : _ _ _ U
tZ
U U e~, V t Z H t Z « \ t a z N
t u. o 1 \ /
z z z T z .z ~ ~ = '' .0 3 a c c c a, a, a, ;, 3 = 3 3 c a a '' c c a a~ v .r ..
~ aø

c c° o _c '~' ~ ~ x ~ E
s '' a. °- s a, a y y y o s E
'°
Z
a z R
z Z +
~~' _ _ \+ ~ ~ o u- o "' ° ~ \ °
\ ~ ~ / \ /
\ / ~ \ /
l z a C C G C C C
T. _?v ,d ~ = 7 C C C C Ji .
C
N
T
i~ ' ~ a ~ as c c a .E R .~ rs .C t. a, V
E
E
r +Z
r-, o/ ~ ~ a ,r O
z Z
o O 00 s c ~ c c a. y. - i, c ~ ~ C
C
T a ~ 1f1 T a 1~6 ,N
V
PEG = 3400 molecular weight polyethylene glycol polymer chain PE~
V ~H~
O O
O
O
PEG = 3400 molecular weight polyethylene glycol polymer chain ~a-t N~EG~N
H H
O.
O
,N
- O
PEG = 3400 molecular weight polyethylene glycol polymer chain O
S
'N \
':.
~~OH
cag WO 98/40375 PCT/US98/03'192 ' C2= Nt! N 0~ i ' lt7.Sl~
~f a n czz Nxs N a3 s ass.s~s ;.
a vx.sa Er n-8u auras oa s sss.~us o~ / o aZ tao o s ;
310. Z3 n-8u :T
Ph ax rae o s s~o.sa n-Bu .T
t 3~
.- . _ Ph OH
~/
OH
Ph cu sac ov s ass.us o~ c~ o _.._._~ . 3u Pn OH ""
az ~z os s . cxz Kzs o3 s »s. oes ~~ 4 ~w ,a ~.
a Ei n-8u i r~n ax wx~ a: s ~c. us 0~ ~0 i ue w,~ ~ oa s o~.so, LT
°-C~IIf a~ quo as s aa.sa ~4 '~.
tr -w t 3 a-C2Z iQl T 03 f .lft. Q7 0'\ / 0 cis gas H o~ s ~roa.s~n cr a Ho - ~r c?Z tfZ! N o1 s ~Qa.3t7 ~r N0 ~- IH
rnw o~.ro, w aw ~"'~s"sa t 33 i a~n,oo~s ~vi. us O
n-8u ~ Er _.___ _.._o ___ ~~~~'' 0~ ___ .._-_... _ r n-C6H~3 Ph a~ rua as s 130.Ea1 II n-Au Er H
C3i 117.~07 a ~-w o~~~
~Er t 3 ~.

cta Sao o, s ,ox.sss ' o aimo,s aea.oxa o~~~.
~~BV
Et /
i ~-8u Ph ~ 35 Ph pH
VA
Ph a,~nxo.s ,m.sei o o~ ~~

i cu axe o3 s sri. sa ~~~ //~
Er ~-8u OH
as quo o~ s ,oi.sss Er ~ 3~

cti gas a, s . cu ~s os s ~c~.oao ae.
. ~~ ~.
w s czz ~aa oa s:
~o~. ssi ors/ o . o\ s/ o ''' Er ,''~ Er .~
~ ~ v n-8u ~~8u HO
S 01i ~ 5 phi ' Ph i 3'~

i i ax las tx o3 s a~.axx '~ c _ . . __ __ i _ QI 11x~ 0.1 t ~f,. his ~3g Ph OH

as N~o o~ s ,cx.su o~ ~~
n-Bu Er Ph CZ3 N70 C~1 f ,Qt.53i I Ph 13q cti Hzo oa s 31i.Q1 Er Phl cti Ino oa s ~ti.Qt Er Ph -..

crt gas o: s ao.zzs P
MBu CZt Irt~ 03 S
7n.sis t - I O

Er Er n-8u Ph pH
V

In further compounds of the present invention, Rs and R' are independently selected from among hydrogen and ring-carbon substituted or unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, pyrimidine, morpholine, N-alkylpyridinium, N-alkyl-piperazinium, N-alkylmorpholinium, or furan in which the substituent(s) are selected from among halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, quaternary ammonium salts, a C1 to C' alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, (O,O)-dioxyalkylene, -[0(CH~)"]~X where x is 2 to 12, w is 2 or 3 and X comprises halo or a quaternary ammonium I5 salt, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, or furan. The aryl group of R5 or R' is preferably phenyl, phenylene, or benzene triyl, i.e., may be unsubstituted, mono-substituted, or di-substituted. Among the species which may constitute the substituents on the aryl ring of R' or R' are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion), methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N)~-hexyldimethylammonium, hexylenetrimethylammonium, tri(oxyethylene)iodide, and tetra(oxyethylene)trimethylammonium iodide, each substituted at the p-position, the m-position, or both of the aryl ring. Other substituents that can be present on a phenylene, benzene triyl or other aromatic ring include 3,4-dioxymethylene (5-membered ring) and 3,4-dioxyethylene (6- membered ring). Among compounds which have been or can be demonstrated to have desirable ileal bile acid transport inhibiting.
properties are those in which R' or R' is selected from phenyl, p-fluorophenyl, m-fluorophenyl, p-hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, m-methoxyphenyl, p-N,N-dimethylaminophenyl, m-N,N-I~I~

diiaethylaminophanyl , I' p- ( cH~ ),-N'-phenyl . I' m- ( Qi, ) ,-N'-phenyl. I' m- (GHQ) ~-1if-~~_ (OCH,CFi,I,-O-ghanyl. I' p-( CFI, ) ,-N -CH~Cii.,- ( OCH~Gii' ) ,-O-phenyl , I' na- (N, N-diiae thyl-piperazinium) - (N' ) -CHI- (pCFi~CH~)a-O-phenyl, 3-methoxy~4-' S fluorophenyl, thienyl-2-yl, 5-cholorothienyl-2-yl, 3,4-difluorophenyl, I' p-(N,N-dimethylpiperazinium)-tN' )-CIi~-(OCH,CH,),-O-phenyl, 3-fluoro-4-iaethoxyphenyl, -d-pyridinyl. 2-pyridinyl,- 3-pyridinyl, N-methyl-d-pyridinium, I' N-metlsyl-3-pyridinium, 3, 4-dioxymethylenephenyl. 3,d-dioxyethylenephenyl, and p-methvxycarbonylphenyl. Preferred compounds include 3-ethyl-3-butyl and 3-butyl-3-butyl compounds having each of the above preferzed R' substituents in combination with the R' substituents shown in Table 1. It is particularly preferzed that one but not both of R' and R' is hydrogen.
It is especially preferzed that R' and R' be hydrogen, that R' and R' riot be hydrogen, and that R' and R' be oriented in the same direction relative to ZO the plane of the molecule, i.e., both in o~ or both in i3-configuration. It is further praferrcd that, where R' is butyl and R' is ethyl , then R' has the saxte orientation relative to the plane of the molecule as R' and R' .
Sat forth in Table lA are lists of species of R'/B'. H'/R' and B'_ P ~-G. ~ 14.~.-t ~~ E-N ~ W N,~~..~ ;
Las ~~-r~ ~

Table ~ ; ALteraative A groups O' ~O
~x~ ~ a ~ s .,.A Rl q - % . s . R2 s ...~~ R3 .,,.
Rs Ra Ra R R R .R R tRs) a eChyl BO- Ph- 7-aethyl a-propyl _. ._g- ~y-?h4_. . __ _...._... ~-ethyl-._ __.
. ...

a-butyl m-F-Ph- 7-iso-propyl n-~a=Yl p-CH3Q-?h- 7-cer:-butyl a-hexyl iso-prop'yl m-cq~a-?h- 7-CCl , iso-bueyl p-tCH~)=N-?h- 7-Otisa-propyl) iso-peatyi m-t~~)=N-?h- 7-SC~
CSIC t OI C=H~ -I T-SOC ~
Cs=cc=as P- IC ) -N-?h-> >
-cs=cs tos) c=ss . ~- tc~) ~-:r-~h- ?-so=c~
I
-C8=O-tt-plea-ine) I T-sC=C3~
p-tC~)~-N-C_~C~=-tCCZC=)=-o-?- T-NH=

I m-IC~I ~-:J'-CIC=- = T-NOti ~

tCC=C=1 =-0-?h- T-NFC~ ..
~'~~

I-. p-tNN- 7-~tC~~)_ di~eLhy_ape:azisel- 7-NICI>> I-tN')-C1-tCCIC=)Z-0- T-aBCt-O)C3~

Ph- 7-N tC=C::~) _ I -tN,:l- 7-N:!eC3=CO=ti diae:..ylpipe:aziaa)- 7-a't:!e)=C=CO=n. I-t~~)-Cz-tccxiC~=)=-o- T-tN)-~:pholi~e p~- ?-tN)-azecidine m-:. p-C~C-?..- T-tN)-N-=echylazecidiniua I-74dioxywe:,,yiee-?h 1-tN)-py::olidirte m-C~C-. p-:-?.-. T-t,t)-N-~et..yl-pyrrolidiniua, I-1-oy:iCize 7-tN)-N-aechyl-ao:pholinium.
I-N-~aechyl-i-oy:idW iua I- T-IN)-Y-aechylpiperaziae I-py:id:ae 7-IN)-a-di~e:..ylpi?eraziniua I-N-es:~yl-3-~y_fGialc:, I- T-:~-C=2 Z-PY:id=ae T-a~tCtO)CSH1I

p-CIO=C-?h- 7-dliCt .o )CIi=Dr C.~3say1-2-yl 7-NH-CIa)NH=

S-C1-chieayl-I-yl 7-t=)-:hiophene 3.t-ditluoro .

~-F.p-~3C-ph eonttacad nexr page...

(øs 1-aechyl 1-ethyl e-iso-propyl 1-CeK-butyl 1-CCH~ .
1-Oliso-propyl) 1-sCS~
1-svC8~
e-so=cs3 1-sc3~ca~
1-NH=
e-Ngoa e-Neca~
_ _-_._..___ --.~__a-N.(c$~)_= _ _ _ 1-N'tcg3)~. I-1-NECf-O)Cs3 1-N fC~=Clip ) _ 1-IINeCHZCO=E
1-N' ftisl =CF=CO=3, I-1-f;f)-eorpholias 8-fN)-azscidiae 8-fN)-N-ae=hylazet'_diaiu~, r 8-fNl-pY=:o--~-ae e-cN)-N-ses:~yl-ayrsolid'-aiua. I-9-ta)-a-aetayl-~o:pholLztu~, I-A-fN)-N'-aaC'ylpiperaziae A-f:11-N'-d'__staylpfperaziaiua. I-A-Ne-C3t 1-!1~C f01 Cs311 A-NECfO)CH=3_ 8-Ye.-C f:IHI NH=
A-f3 ) -c:ae~hera eont_auad asst papa...
l4-6 9-eechyl 9-ethyl 9-iso-propyl 9-tart-butyl 9-Otiso-propyl) 9-SCr~
9-SOC:i3 9-50=C»x 9-SCS=C)i~
9-NFI=
4-N~OH
9-N»C»x 9-N (C'~3) _ 9=a'tCa~)j~'_ 4-N8C t~0) C'~
9-N tC»=C)i~ ) _ 9-N,!eC3=CO=8 9-a't:!e)ZC»=CO=x, I-9-lN)-~orpholine 9-tN)-azecidine 9-IY)-N-r.echylazetidinia~, I-9-tN)-pyrrolidine 9-tN)-N-aethyl-pyrrolidiniua, I-9-ta) -,t-:eechyl-worpholiniu~s, I-' 9-Ia)-H'-we:hylpiperazine 9-ta) -N~ -Ciwec.'.ylpigeraz i nii:a, I-9-yi:C t0) C;~:1 9-N»C t01 C »i3r 4-Ni:-C INf:1 Ne:=
9-t2)-chiophene 7-CC y, 8-CC»~
7-SC»~, 8-CC~~
7-3~»~. 8-SC3~ .
6-CCJI, 7-CC»l, A-OCaI

Further preferred compounds of the present invention comprise a core structure having two or more pharmaceutically active benzothiepine structures as described above, covalently banded to the core moiety via functional linkages. Such active benzothiepine structures preferably comprise:
_ _c_~ ~, . ~
(r~' s i "2 4 (Formula DIV) or:
cod R7 s cR"~
~5~4 ~'3 (Formula DIVA) where R1, R~, R', R~, R', R', R', R', R°, X, q and n are as defined above, and Rss is either a covalent bond or.
arylene.

The core moiety can comprise alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide, polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, can optionally have one or more carbon replaced by_O, NR',___.N'R'R°, S, SO, gp2 S'R'R°, pR~ , p+R~R8 , phenylene, heterocycle, quatarnary heterocycle, quaternary heteroaryl, or aryl, -wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14~ SR13~ S(0)R13~
S02R13, S03R13, NR130R14, NR13NR14R15~ N02. C02R13, CN, OM, S020M, S02NR13R14~ C(0)NR13R14, C(O)OM, COR13, P (0) R13R14 ~ p+R13R14;R15A- ~ p (OR" ) OR1', S~RI'Rl'A~, and N+R9R11R12A-wherein said alkyl, alkenyl, alkynyl, polyalkyl,-polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of ORS, NR~R8, SRS, S(O)RB, S02R~, S03R~, C02R~, CN, oxo, CONR~RB, N+R~R8R9A-, alkyl, alkenyl, alkynyl,.aryl, cycloalkyl, heterocycle, arylalkyl, quaternary 1 ~I 9 heterocycle, quaternary heteroaryl, P(O)R~R8, P+R~RBA , and P ( O ) ( OR' ) ORS , and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR7, N+R~RBA-, S, SO, 502, S+R~A-, PRA, P(O)R', P+-R~R$A-; or phenylene. -Exemplary core moieties include:

~~~_~~2 7 0 ~27 k0 ~27 k R26 ~ 'Sl 27 k yd R2 ~R27 wherein:
R" is selected from the group consisting of C and N, and R" and R" are independently selected from the group consisting of:
(O)x -N- ~ ~T_. _p_. _.S_.~ -~. -CFi2_ o s o s ~I~ ~-~ I h~ 11 -c -c -~ --g f .. .~1H Slii _. -~p ~ . and ~N~
~t32 Z '~ ~NH2 wherein R". R", R'° aad R" are independently selected from alkyl, alkenyl, alkylaryl, aryl, arylalkyl. ~ cycloalkyl._ hetero:c,~c~:e: and -hate=ocycl alkyl, Z5 A is a pharmaceutically acceptable anion, and k =
1 to 10.
I s~

In compounds of Formula DIV, Rs°, R'l, R=' in Formulae DII and DIII, and R" in Formula DIII can be bonded at any of their 6-, 7-, 8-, or 9- positions to Rl'. In compounds of Formula DIVA, it is preferred that R" comprises a phenylene moiety bonded at a m- or p-position thereof to R1'.
In another embodiment, a core moiety backbone, R", as discussed herein in Formulas DII and DIII can be multiply substituted with more than four pendant active benzothiepine units, i . a . , R'°, R'1, R", and R" as discussed above, through multiple functional groups within the core moiety backbone. The core moiety backbone unit, Rl', can comprise a single core moiety unit, multimers thereof, and multimeric mixtures of the different core moiety units discussed herein, i.e., alone or in combination. The number of individual core moiety backbone units can range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. The number of points of attachment of similar or different pendant active benzothiepine units within a single core moiety backbone unit can be in the range from about one to about 100, preferably about~one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. Such points of attachment can include bonds to C, S, O, N, or P within any of the groups encompassed by the definition of Ri'.
The more preferred benzothiepine moieties comprising R'°, R=l, R~= and/or R" conform to the preferred structures as outlined above for Formula I.
The 3-carbon on each benzothiepine moiety can be achiral, and the substituents R', R=, R', R~, R' and R"
~ sz can be selected from the preferred groups anct combinations of substituents as discussed above. The core structures can comprise, for example, poly(oxyalkylene) or oligo(oxyalkylene), especially poly- or oligo(oxyethylene) or poly- or oligo(oxypropylene).
Dosasres, Formulations, and Routes of Administration The ileal bile acid transport inhibitor compounds of the present invention can be administered for the prophylaxis and treatment of hyperlipidemic diseases or conditions by any means, preferably oral, that produce contact of these compounds with their site of action in the body, for example in the ileum of a mammal, e.g., a human.
For the prophylaxis or treatment of the conditions referred to above, the compounds of the present invention can be used as the compound per se.
Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, malefic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and calcium salts.
The anions of the definition of A in the present invention are, of course, also required to be pharmaceutically acceptable and are also selected from the above list.
The compounds of the present invention can be presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05 to 95~ by weight of the active compound.
Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well known techniques of pharmacy, consisting essentially of admixing the components.
These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic compounds or as a combination of therapeutic compounds.
The amount of compound which is required~to achieve the desired biological effect will, of course, depend on a number of factors such as the specific compound chosen, the use for which it is intended, the I5~

mode of administration, and the clinical condition of the recipient.
In general, a daily dose can be in the range of from, about 0.3 to about 100 mg/kg bodyweight/day, preferably from about 1 mg to about 50 mg/kg bodyweight/day, more preferably from about 3 to about mg/kg bodyweight/day. This total daily dose can be administered to the patient in a single dose, or in proportionate multiple subdoses. Subdoses can be 10 administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results.
Orally administrable unit dose formulations, such as tablets or capsules, can contain, for example, from about 0.1 to about 100 mg of benzothiepine compound, preferably about 1 to about 75 mg of compound, more preferably from about 10 to about 50 mg of compound.
In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the benzothiepine ion derived from the salt.
Oral delivery of an ileal bile acid transport inhibitor of the present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms.
These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH
. of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time IJJ

period over which the active drug molecule is delivered to the site of action (the ileum) by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl~ester.
When administered intravenously, the dose can, for example, be in the range of from about 0.1 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, more preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight. This dose can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, preferably from about 1 ng to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g of the compound of the present invention. Thus, ampoules for injection can contain, for example, from about 1 mg to about 100 mg.
Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g., sublingual), and parenteral (e. g., subcutaneous, intramuscular,.
intradermal, or intravenous) administration, although the most suitable route in any given case will..depend on the nature and severity of the condition being treated and on the nature of the particular compound IS (o which is being used. In most cases, the preferred route of administration is oral.
Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or, non-aqueous liquid; or as an oii-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compounds) and the carrier (which can constitute one or more accessory ingredients). In IS general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, ~intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood.
Injectable compositions according to the invention will generally contain from 0.1 to 5~ w/w of a compound disclosed herein.
Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of the present invention with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15~ w/w of the composition, for example, from 0.5 to 2~.
Transdermal administration is also possible.
Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches 15~

adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound of the present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 3(6), 318 (1986).
In any case, the amount of active ingredient that can be combined with carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration.
The solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules noted above comprise one or more compounds of the present invention admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms~for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents. .
The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic .parenterally acceptable diluent or solvent, for example, as a solution in I,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Pharmaceutically acceptable carriers encompass all the foregoing and the like.
In combination therapy, administration of the ileal bile acid transport inhibitor and HI~IG Co-A
reductase inhibitor may take place seguentially in separate formulations, or may be accomplished by simultaneous administration in a single formulation or separate formulations. Administration may be accomplished by oral route, or by intravenous, intramuscular, or subcutaneous injections. The formulation may be in the form of a bolus, or in the form of aaqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more pharmaceutically-acceptable lb0 carriers or diluents, or a binder such as gelatin or hydroxypropylmethyl cellulose, together with one or more of a lubricant, preservative, surface active or dispersing agent.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension, or liquid. Capsules, tablets, etc., can be prepared by conventional methods resell known in the art. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient or ingredients. Examples of dosage units are tablets or capsules. These may with advantage contain one or more ileal bile acid transport inhibitors in an amount described above. In the case of HI~lG Co-A reductase inhibitors, the dose range may be from about 0.01 mg to about 500 mg or any other dose, dependent upon the specific inhibitor, as is known in the art.
The active ingredients may also be administered by injection as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier. A suitable daily dose of each active inhibitor is one that achieves the same blood serum level as produced by oral administration.as described above.
The active inhibitors may further be administered by any dual combination of oral/oral, oral/parenteral, or parenteral/parenteral~route.
Pharmaceutical compositions for use in the' treatment methods of the present invention may be administered in oral form or by intravenous administration. Oral administration of the combination therapy is preferred. Dosing for oral administration Ib1 may be with a regimen calling for single daily dose, or for a single dose every other day, or for multiple, spaced doses throughout the day. The inhibitors which make up the combination therapy may be administered simultaneously, either in a combined dosage form or in separate dosage forms intended for substantially simultaneous oral administration. The inhibitors which make up the combination therapy may also be administered sequentially, with either inhibitor being administered by a regimen calling for two-step ingestion. Thus, a regimen may call for sequential administration of the inhibitors with spaced-apart ingestion of the separate, active agents. The time period between the multiple ingestion steps may range from a few minutes to several hours, depending upon the properties of each inhibitor such as potency.
solubility, bioavailability, plasma half-life and kinetic profile of the inhibitor, as well as depending upon the age and condition of the patient. The inhibitors of the combined therapy whether administered simultaneously, substantially simultaneously, or sequentially, may involve a regimen calling for administration of one inhibitor by oral route and the other inhibitor by intravenous route. Whether the inhibitors of the combined therapy are administered by oral or intravenous route, separately or together, each such inhibitor will be contained in a suitable pharmaceutical formulation of pharmaceutically=
acceptable'excipients, diluents or other formulations components. Examples of suitable pharmaceutically-acceptable formulations containing the inhibitors for oral administration are given above.

Treatment Recimen The dosage regimen to prevent, give relief from, or ameliorate a disease condition having hyperlipemia as an element of the disease, e.g., atherosclerosis, or to protect against or treat further high cholesterol plasma or blood levels with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors. These include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.
Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or eliminated.
Patients undergoing treatment with the compounds or ' compositions disclosed herein can be routinely monitored by, for example, measuring serum LDL and total cholesterol levels by any of the methods well known in the art, to determine the effectiveness of the combination therapy.. Continuous analysis of such data permits modification of the treatment regimen during Ib3 therapy so that optimal effective amounts of each type of inhibitor arE administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of ileal bile acid transport inhibitor and HIMG Co-A reductase inhibitor which together exhibit satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the hyperlipidemic condition.
A potential advantage of the combination therapy disclosed herein may be reduction of the amount of ileal bile acid transport inhibitor, HI~IG Co-A reductase inhibitor, or both, effective in treating hyperlipidemic conditions such as atherosclerosis and hypercholesterolemia.
The following non-limiting examples serve to illustrate various aspects of the present invention.
~(o~-EXAMPLES OF SYNTHETIC PROCE_DVRES
15 _~_ _ Pre~ara~ ion 1 ~3c ~ '~ ~ NZ a ~ 4~
2-Ethyl-2-(mesyloxymethyl)hexanal (1) To a cold (10 °C) solution of 12.6 g (0.11 mole) of rnethanesulfonyl chloride and 10.3 g (0.13 mole) of 20 triethylamine was added dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30 °C.
The reaction mixture was stirred at room temperature 25 ' for 18 h, quenched with dilute HC1 and extracted with methlyene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo to give 24.4 g of brown oil.
30 Pre~a=ation 2 2-((2-Henzoylphenylthio)methyl)-2-ethylhexanal (2)5 °
A mixture of 31 g (0.144,mo1) of 2- a a N
- mercaptobenzophenone, prepared according to the c>>
procedure described in WO 93/16055, 24.4 g (0.1 mole) 35 of 2-ethyl-2-(mesyloxymethyl)-hexanal (1), 14:8 g (0.146 mole) of triethylamine, and 80 mL of 2-methoxyethyl ether was held at reflux for 24 h. The reaction mixture was poured into 3N HC1 and extracted t b'S

with 300 mL of methylene chloride. The methylene chloride layer was washed with 300 mL of 10% NaOH, dried over MgSO, and concentrated in vacuo to remove 2- _ methoxyethyl ether. The residue was purified by HPLC
(10% EtOAc-hexane) to give 20.5 g (58%) of 2 as an oil.
Example 1 3-Hutyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine (3), cis-3-Hutyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-~ (5X)4-one (4a) and traps-3-Hutyl-3-ethyl-5-phenyl-2,3-,dihydro-benzothiepin-(5X)4-one (4b) ~S S~~

a a A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl~ and 80 mL of anhydrous ethylene IS glycol dimethyl ether (DME) was held at reflux for 2 h.
The reaction mixture was cooled to 5 °C. To the reaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of 2 in 30 mL of DME in 40 min. The reaction mixture was stirred at room temperature for 16 h and then was held at reflux for 2 h and cooled before being poured into brine. The organic was extract into methylene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g (43%) of 3 as an oil in the first fraction. The second fraction was discarded and the third fraction was further purified by HPLC (hexane) to give 0.07 g (2%) of 4a in the earlier fraction and 0.1 g (3%) of 4b in the later fraction. .
Fxar~ple 2 cis-3-Hutyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-(SX)4-one-1,1-dioxide (5a) and traps-3-Hutyl-3-ethyl-5-phenyl-2,3-dihydro-benzothiepin-(5X)4-one-1,1-dioxide ( 5b ) Sos . ~ -° ~ SQ, S b o -o To a solution of 1.2 g (3.5 mm e) of 50-60% MCPBA in 20 mL of methylene chloride was added 0.59 g (1.75 i 6f~

mmole) of a mixture of 4a and 4b in 10 mL of methylene chloride. The reaction mixture was stirred for 20 h. An additional 1.2 g (i.?5 mmole) of 50-60% MAPBA was added and the reaction mixture was stirred for an additional 3 h then was triturated with 50 mL of 10% NaOH. The insoluble solid was filtered. The methylene chloride layer of the filtrate was washed with brine, dried over MgSO,, and concentrated in vacuo. The residual syrup was purified by HPLC (5% EtOAc-hexane) to give 0.2 g (30%)of 5a as an oil in the first fraction and 0.17 g ~(26%) of 5b as an oil in the second fraction.
o a _. _ z Sci O W
Eacam~le 3 0 off tlea~ \ ~'~oH ~66' (3a,4a,5b) 3-Hutyl=3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6a), (3a,4b,5a) 3-Hutyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydro- -S''~-~E
benzothiepine-1,1-dioxide (6b), (3a,4a,5a) 3-Hutyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5- ~ ou tetrahydrobenzothiepine-1,1-dioxide (6c), and ~ ~~I) (3a,4b,5b) 3-Hutyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6d) A. Reduction of 5a and Sb With Sodium Horohydride To a solution of 0.22 g (0.59 mmole) of 5b in 10 mL of ethanol was added 0.24 g (6.4 mmole) of sodium borohydride. The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo to remove ethanol. The residue was triturated With water and extracted with methylene chloride. The methyleae chloride extract was dried over MgSO, and concentrated in vacuo to give 0.2 g of syrup. In a separate experiment, 0.45 g of 5a.was treated with 0.44 g of sodium borohydride in 10 mL of ethanol and was worked up as described above to give 0.5 ~ of syrup which was identical to the 0.2 g of syrup obtained above. These two materials were combined and purified by HPLC using 10% EtOAc-hexane as eluant. The first fraction was 0.18 g (27%) of 6a as a syrup. The second fraction was 0.2 g 1 ~"l (30%) of 6b also as a syrup. The column was then eluted with 20% EtOAc-hexane to give 0.077 g (11%) of 6c in the third fraction as a solid. Recrystallization from hexane gave a solid, mp 179-181 °C. Finally, the column was eluted with 30% EtOAc-hexane to give 0.08 g (12%) of 6d in the fourth fraction as a solid.
Recrystallization from hexane gave a solid, mp 160-161 °C.
B. Conversion of 6a to 6c and 6d With NaOH and PTC
To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL
CH~C1= , was added 9 g of 40% NaOH. The reaction mixture was stirred for 0.5 h at room temperature and was added one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst (PTC). The mixture was stirred for 0.5 h at room temperature before being treated with 25 mL of ice-crystals then was extracted with CH=C1= ( 3x10 ml ) , dried over MgSO, and concentrated in vacuo to recover 0.17 g of a colorless film. The components of this mixture were separated using an HPLC
and eluted with EtOAc-hexane to give 12.8 mg (4%) of 2-(2-benzylphenylsulfonylmethyl)-2-ethylhexenal in the first fraction, 30.9 mg (11%) of 6c in the second fraction and 90.0 mg (31%) of 6d in the third fraction.
Oxidation of 6a to 5b To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of CH,C1~ was added 0.23 g (1.0 mmole) of pyridinium chlorochromate. The reaction mixture was stirred for 2 h then was treated with additional 0.23 g of pyridinium chlorochromate and stirred overnight. The dark reaction mixture was poured into a ceramic filterfrit containing silica gel and was eluted with CH=C1,. The filtrate was concentrated in vacuo to recover 167 mg (87%) of 5b as a colorless oil.

~xamDle 4 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine-1,1-~ _ _ dioxide ( 7 ) ~ Soi To a solution of 5.13 g (15.9 mmole) of 3 in 50 mL of CH~Cl,was added 10 g (31.9 mmole)of 50-60% MCPBA (m-chloroperoxybenzoic acid) portionwise causing a mild reflux and formation of a white solid. The reaction mixture was allowed to stir overnight under N= and was triturated with 25 mL of water followed by 50 mL of 10%
~NaOH solution. The organic was extracted into CH=Cl=
(4x20 mL). The CH=Cl=extract was dried over MgSO, and evaporated to dryness to recover 4.9 g (87%) of an opaque viscous oil.
IS
~~,amD 1 a 5 (laa,2b,Bba ) 2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (8a) (laa,2a,8ba) 2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino [4,5-b]oxirene-4,4-dioxide ( 8b ) Soy st~i ~4--g~ ° c~b~
To 1.3 4.03 mole) of in 25 mL of CHC1~ was added portionwise 5 g (14.1 mmole) of 50-60 % MCPBA causing a mild exotherm. The reaction mixture was stirred under N= overnight and was then held at reflux for 3 h. The insoluble white slurry was filtered. The filtrate was extracted with 10% potassium carbonate (3x50 mL), once with brine, dried over MgSO,, and concentrated in vacuo to give 1.37 g of a light yellow oil. Purification by HPLC gave 0.65 g of crystalline product. This product is a mixture of two isomers. Trituration of this crystalline product in hexane recovered 141.7 mg (10%) of a white crystalline product. This isomer was characterized by NMR and mass spectra to be the (laa,2b,8ba) isomer 8a. The hexane filtrate was concentrated in vacuo to give 206 mg of white film which is a mixture of 30% 8a and 70% 8b by 'H NMR.
16g s°z v ,y ~S~h . S~
~nr O
Example 6 ° C~a~ ~cl~
cis-3-Hut 1-3-eth 1-5- hea 1-2 3~ 5-tetrah dro-Y Y p Y ~ ~ ~ Y C
benzothiepine-1,1-dioxide (9a), traps-3-Hutyl-3-ethyl 5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (9b), and 3-Hutyl-3-ethyl-4-hydroxy-5-cyclohexylidine-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (10) A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a and 8b was dissolved in 15 ml MeOH in a 3 oz.
~Fisher/Porter vessel, then was added 0.1 g of l0% Pd/C
catalyst. This mixture was hydrogenated at 70 psi H=
for 5 h and filtered. The filtrate was evaporated to dryness in vacuo to recover 0.117 g of a colorless oil.
This material was purified by HPLC eluting with EtOAc-hexane. The first fraction was 4.2 mg (3%) of 9b. The second fraction, 5.0 mg (4%), was a 50/50 mixture of 9a and 9b. The third fraction was 8.8 mg (6%) of 6a . The fourth fraction was 25.5 mg (18%) of 6b. The fifth fraction was 9.6 mg (7%) of a mixture of 6b and a product believed to be 3-butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide based on mass spectrum. The sixth fraction was 7.5 mg (5%) of a mixture of 6d and one of the isomers of 10, 10a.
Example 7 In another experiment, a product (3.7 g) from epoxidation of 3 with excess MCPBA in refluxing CHC1, under air was hydrogenated in 100 mL of methanol using 1 g of 10% Pd/C catalyst and 70 psi hydrogen. The product was purified by HPLC to give 0.9--g--(25%) of 9b, 0.45 g (13%) of 9a, 0.27 g (7%) of 6a, 0.51 g (14%) of 6b,Ø02 g (1%) of 6c, 0.06 g (2%.) of one isomer of 10, l0a and 0.03 g (1%) of another isomer of 10, i0b.
l'7 l~ .

S ~ , .~~d H
v Example 8 ~ ~~~~
2-((Z-Benzoylphenylthio)methyl)butyraldehyde (11) To an ice bath cooled solution of 9.76 g (0.116 mole ) of 2-ethylacrolein in 40 mL.of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF
followed by I3 g (0.128 mole) of triethylamine. The reaction mixture was stirred at room temperature for 3 days , diluted with ether, and was washed successively with dilute HC1, brine, and 1 M potassium carbonate.
The ether layer was dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give 22 g (64%) of il in the second fraction. An attempt to further purifiy this material by kugelrohr distillation at 0.5 torr (160-190 °C) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation.
This material was dissolved in ether (100 mL) and was washed with SO mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure il.
Exam lp a 9 O
3-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12) m a To a mixture of 2.61 g (0.04 mole) of zinc dust and 60 mL of DME was added 7.5 g (0.048 mole) of TiCl,. The reaction mixture was held at reflex for 2 h. A solution of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h.
The reaction mixture was held at reflex for 18 h, ___ cooled and poured into water. The organic was extracted into ether. The ether layer was washed with brine and-filtered through Celite. The filtrate was dried over MgSO, and concentrated. The residual oil (2.5 g) was purified by HPLC to give 2.06 g (77%) of 12 as an oil in the second fraction.

S°z Example 10 v ~ ~13~
(laa,2a,8ba) 2-Ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino-j4,5-b]oxirene-4,4-dioxide (13) To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of CHC1, was added 6.8 g (19.4 mmole) of 50-60% MCPB
portionwise causing an exothem and formation of a white solid. The mixture was stirred at room temperature overnight diluted with 100 ml methylene chloride and washed successively with 10% K,CO, (4x50 ml), water '(twice with 25 ml) and brine. The organic layer was then dried over MgSO, and evaporated to dryness to recover 1.47 g of an off white solid. 1H NMR indicated that only one isomer is present. This solid was slurried in 200 ml of warm Et,O and filtered to give 0.82 g (46%) of 13 as a white solid, mp 185-186.5 °C.
Example 11 (3a,4b,5a)- 3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (14a), (3a,4b,5b) 3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (14b), aad cis-3-Ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide ( 15 ) ~ ''t ft ~5~~ ft Ns°L ~ E
C~~~ i 4 ~'~b~ ~,~ t O o H C q~ Q o H C S, A mixture of 0.5 g (1.6 mole) of 13, 50 ml of ace is acid and 0.5 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 4 h. The crude. reaction slurry was filtered and the filtrate was stirred with 150 ml of a saturated NaHCO, solution followed by 89 g of NaHCO,.powder portionwise to neutralize the rest of acetic acid. The mixture was extracted with methylene chloride (4x25 mI), then the organic layer was dried over MgSO, and concentrated in vacuo to give 0.44 g (8?%) of a voluminous white solid which was purified by HPLC (EtOAc-Hexane) to give 26.8 mg (6%) of 15 in the first fraction, 272 mg (54%) of 14a as a solid, mp 142-143.5 °C, in the second fraction, and 35 mg (7%) of impure 14b in the third fraction.
Ex~ple 12 2-Ethyl-2-((2-Hydroxymethylphenyl)thiomethyl)hexenal (16) "'1s p ~'C~ 67 °H H
A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of ~triethylamine and 25 mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was added to the reaction mixture and the mixture was held at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HCl and extracted with methylene chloride. The methylene chloride extract was washed twice with 10% NaOH, dried over MgSO, and concentrated in vacuo to give 9.6 g of residue.
Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%)of 16 as an oil.
~5 - ~~C"
Example 13 ° 'o 2-Ethyl-2-((2-formylphenyl)thiomethyl)hexenal (17) A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridinium chlorochromate, 2 g of Celite and 30 mL of methylene chloride was stirred for 18 h and filtered through a bed of silica gel. The silica,gel was eluted 3o with methylene chloride. The combined methylene chloride eluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g (66%) of an oil. -Example 14 C1 ~, 3-Butyl-3-ethyl-2,3-dihydrobenzothiepiae (18) A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl,, and 50 mL of DME was held at x'13 WO 98/40375 PCTlUS98/0379Z
reflex for 2 h and cooled to room temperature.. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflex for 1 h then was let standing at room temperature over weekend. The reaction mixture was poured into dilute HC1 and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried over MgSO,, and concentrated in vacuo to give 3.0 g of ~a residue. Purification by HPLC gave 0.41 g (20%) of 18 as an oil in the early fraction.
Example 15 IS (laa,2a,8ba ) 2-Butyl-2-ethyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b7oxirene-4,4-dioxide (19a) and (laa,2b,8ba) 2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b7oxirene-4,4-dioxide (19b) a Sc1 ,~ ~S°i 6~.
~ _ ''« Et 0 ~'~ =o' To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in 30 mL of methylene chloride was added 2.2 g (3.2 mmole) of 50-60% MCPBA. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 3 0 mL of CHC1, and was held at ref lux f or 18 h under N~ .
The reaction mixture was stirred with 100 mL of 10%
NaOH and 5 g of sodium sulfite. The methylene chloride layer was washed with brine, dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC
(20% EtOAc-hexane) to give a third fraction cahich was further purified by HPLC (10% EtOAc-hexane) to give 0.12 g of syrup in the first fraction.
Recrystallization from hexane gave 0.08 g (17%) of 19a, mp 8.9.5-105.5 °C. The mother liquor from the first fraction was combined with the second fraction~and was further purified by HPLC to give additional 19a in the first fraction and 60 mg of 19b in the second fraction.
1 '7 ~-Crystallization from hexane gave 56 mg of a white solid.
Example 16 3-Hutyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (20) ~~So1 O
This product was isolated along with 6b from H a hydrogenation of a mixture of 8a and 8b. " (2uj ~'~amflle 17 3-Hutyl-3-ethyl-4-hydroxy-5-phenylthio-2,3,4,5-Sv1 8 tetrahydro-benzothiepine-1,1-dioxide (21) p ~'s c N
A mixture of 25 mg (0.085 mmole) of 19b, 0.27 g (2.7 (Z1~
mmole) of thiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL of DMF was stirred at room temperature under N, for 19 h. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed successively with 10% NaOH and brine, dried over MgSO,, and concentrated in vacuo to give 0.19 g of semisolid which contain substantial amounts of diphenyl disulfide. This material was purified by HPLC (5%
EtOAc-hexane) to remove diphenyl disulfide in the first fraction. The column was then eluted With 20% EtOAc-hexane to give 17 mg of a first fraction, 4 mg of a second fraction and 11 mg of a third fraction which.
were three different isomers of 21, i.e. 21a, 21b, and 21c, respectively, by iH NMR and mass spectra.
Example 18 Alternative Synthesis of 6c and 6d A. Preparation from 2-((2-Henzoylphenylthio)methyl)-2-ethylhexanal (2) Step 1. 2-((2-Henzoylphenylsulfonyl)methyl)-2 ethylhexaaal (44) SOt eK
o J Et L ~1~ '' c~-~

To a solution of 9.0 g (0.025 mole) of compound 2 in 100 ml of methylene chloride was added 14.6 g (0.025 mol) of 50-60% MCPBA portionwise. The reaction mixture was stirred at room temperature for 64 h then was stirred with 200 ml of 1 M potassium carbonate and filtered through Celite. The methylene chloride layer was washed twice with 300 ml of 1 M potassium carbonate, once with 10% sodium hydroxide and once with brine. The insoluble solid formed during washing was removed by filtration through Celite. The methylene .chloride solution was dried and concentrated in vacuo to give 9.2 g (95%)of semisolid. A portion (2.6 g) of this solid was purified by HPLC(10% ethyl acetate-hexane) to give 1.9 g of crystals, mp 135-I36 °C
Step 2. 2-((2-Henzylphenylsulfonyl)methyl)-2-S ~Z~EE
ethylhexanal (45) A solution of 50 g (0.13 mole) of crude 44 in 250 ml of methylene chloride was divided in two portions and charged to two Fisher-Porter bottles. To each bottle was charged 125 ml of methanol and 5 g of 10% Pd/C. The bottles Were pressurized with 70 psi of hydrogen and the reaction mixture was stirred at room temperature for 7 h before being charged with an additional 5 g of 10% Pd/C. The reaction mixture was again hydrogenated with 70 psi of hydrogen for 7 h. This procedure was, repeated one more time but only 1 g of Pd/C was charged to the reaction mixture. The combined reaction mixture was filtered and concentrated in vacuo to give 46.8 g of 45 as brown oil.
Step 3. (3a,4a,5a) 3-8uty1-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (6c), aad (3a,4b,5b) 3-Hutyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepiae-1,1-dioxide (6d) 1'1 ~

WO 98/40375 PCT/US98/03'f92 To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of anhydrous THF cooled to 2 °C with an ice bath was added 9.7 g (73.4 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred for 20 min, quenched with 300 ml of 10% HC1 and extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to give 24.7 g of yellow oil. Purification by HPLC (ethyl acetate-hexane) yielded 9.4 g of recovered 45 in the first fraction, 5.5 g (20%) of 6c in the second fraction and 6.5 g (24%) of 6d in the third fraction.
H. Preparation from 2-hydroxydiphenylmethana Step 1. 2-iaercaptodiphenyhaethane (46) ~ C
is To a 500 ml flask was charged I6 g (0.33 mol) of 60%
sodium hydride oil dispersion. The sodium hydride was washed twice with 50 ml of hexane. To the reaction flask was charged 100 ml of DID'. To this mixture was added a solution of 55.2 g (0.3 mol) of 2-hydroxydiphenylmethane in 200 ml of DMF in 1 h while temperature was maintained below 30 °C by an ice-water bath. After complete addition of the reagent, the mixture was stirred at room temperature for 30 min then cooled with an ice bath. To the reaction mixture was added 49.4 g (0.4 mole) of dimethyl thiocarbamoyl chloride at once. The ice bath was removed and the reaction mixture was stirred at room temperature for l8 h before being poured into 300 ml of water. The organic was extracted into 500 ml of toluene. The toluene layer _was washed..successively with 10% sodium hydroxide and brine and.was concentrated in vacuo to give 78.6 g of a yellow oil which was 95% pure dimethyl 0-2-benzylphenyl thiocarbamate. This oil was heated at 280-300 ~°C in a kugelrohhr pot under house vacuum for 30 min. The residue was kugelrohr distilled at 1 torn (180-280 °C).
The distillate (56.3 g) was crystallized from methanol to give 37.3 g (46%) of the rearranged product dimethyl l "1'l S-2-benzylphenyl thiocarbamate as a yellow solid. A
mixture of 57 g (0.21 mole) of this yellow solid, 30 g of potassium hydroxide and 150 ml of methanol was stirred overnight then was concentrated in vacuo. The residue was diluted with 200 ml of water and extracted with ether. The aqueous layer was made acidic with concentrate HC1, The oily suspension was extracted into ether. The ether extract was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 37.1 g (88%) of 2 mercaptodiphenylmethane as a yellow solid.
Step 2. 2-((2-Henzylphenylthio)methyl)-2-ethylhexanal (47) v ~S~Et ~s ~ H J c A mixture of 60 g (03 mole) of yellow solid from step 1, 70 g (0.3 mole) of compound 1 from preparation 1, 32.4 g (0.32 mole) of triethylamine, 120 ml of 2-methoxyethyl ether was held at reflux for 6 hr and concentrated in vacuo. The residue was triturated with -500 ml of water and 30 ml of concentrate HC1. The organic was extracted into 400 ml of ether. The ether layer was washed successively with brine, 10% sodium hydroxide and brine and was dried over magnesium sulfate and concentrated in vacuo. The residue (98.3 g) was purified by HPLC with 2-5% ethyl acetate-hexane as eluent to give 2-((2-benzylphenylthio)methyl)-2-ethylhexanal 47 as a yellow syrup.
Step 3. 2-((2-Benzylphenylsulfonyl)methyl)-2-ethylhexanal - ( 4 5 ) ~ S ~'L
Et ~~ s~
To a solution of 72.8 g (0.21 mole) of yellow syrup from step 2 in 1 liter of methylene chloride cooled to 10 °C was added 132 g of 50-60% MCPBA in 40 min. The reaction mixture was stirred for 2 h. An additional 13 g of 50-60% MCPHA was added to the reaction mixture.
The reaction mixture was stirred for 2 h and filtered (1$

through Celite. The methylene chloride solution was washed twice with 1 liter of 1 M potassium carbonate then with 1 liter of brine. The methylene chloride layer was dried over magnesium sulfate and concentrated to 76 g of 2-((2-benzylphenylsulfonyl)methyl)-2-ethylhexanal 45 as a syrup.
Step 4. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepiae-1,1-dioxide (6c), and (3a,4b,5b) 3-Hutyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6d) Reaction of 45 with potassium t-butoxide according to the procedure in step 3 of procedure A gave pure 6c and 6d after HPLC. S Ete~
~J v Exams 1 a 19 ~c O a b ~ C 22' (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (25) and (3a,4a,5a) 3-Hutyl-3-ethyl-4-hydroxy-B-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (26) Step 1. Preparation of 2-((2-benzoyl-4-methoxy phenylthio)methyl)-2-ethylhexanal (22) 2-Hydroxy-4-methoxybenzophenone was converted to the dimethyl 0-2-benzoyphenyl thiocarbamate by methods previously described in example 18. The product can be isolated by recrystallization from ethanol. Using this improved isolation procedure no chromatography was needed. The thermal rearrangement was performed by reacting the thiocarbamate( 5 g) in diphenyl ether at 260 °C as previously described. The improved isolation procedure which avoided a chromatography step was described below.
-_ 35 The crude pyrolysis product was then heated at 65 °C in 100 ml of methanol and 100 ml of THF in the presence of 3._5 g of KOH for 4 h. After removing THF and methanol by rotary evaporation the solution was extracted with 5 ~ NaOH and ether. The base layer was acidified and extracted with ether to obtain a 2.9 g of crude thiophenol product. The product was further purified by titrating the desired mercaptan into base with limited KOH. After acidification and extraction with ether pure 2-mercapto-4-methoxybenzophenone (2.3 g) was isolated.
2~mercapto-4-methoxybenzophenone can readily be IO converted to the 2-((2-benzoyl-4-~methoxyphenylthio)methyl)-2-ethylhexanal (22) by reaction with 2-ethyl-2-(mesyloxymethyl)hexanal (1) as previously described.
Step 2. 2-((2-Henzoyl-5-methoxyphenylsulfonyl)methyl)-et y~ g k 2-ethylhexanal (23) i;3 °
° (z3) v v Substrate 22 was readily oxidized to 2-((2-benzoyl-5-methoxyphenyl-sulfonyl)methyl)-2-ethylhexanal (23) as described in example 18 . ~y ~~ 5~1-.cue tt j v o ~~ a ~, ~ 2 4~

Step 3. 2-((2-benzyl-5-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (24) Sulfone 23 was then reduced to 2-((2-benzyl-5-methoxyphenyl-sulfonyl)methyl)-2-ethylhexanal (24) as described in example 18. t~3 °~~sv'' _ ''~ ('I5>
oN
Step 4. (3a,4b,5b) 3-Hutyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (25) and (3a,4a,5a) 3-Hutyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1=
dioxide (26) ~~~5~'L

O
A 3-neck flask equipped with a powder addition"°u funnel, thermocouple and nitrogen bubbler was charged with 19.8 g (0.05 mole) of sulfone 24 in 100 ml dry THF. The reaction was cooled to -1.6 °C internal ($O

temperature by means of ice/salt bath. Slowly add 5.61 g (0.05 mole) of potassium t-butoxide by means of the powder addition funnel. The resulting light yellow solution was maintained at -1.6 °C. After 30 min reaction 400 ml of cold ether was added and this solution was extracted with cold 10 ~ HCl. The acid layer was extracted with 300 ml of methylene chloride.
The organic layers were combined and dried over magnesium sulfate and after filtration stripped to dryness to obtain 19.9 g of product. iH nmr and glpc indicated a 96% conversion to a 50/50 mixture of 25 and 26. The only other observable compound was 4$ starting sulfone 24.
The product was then dissolved in 250 ml of 90/10 hexane/ethyl acetate by warming to 50 °C. The solution was allowed to cool to room temperature and in this way pure 26 can be isolated. The crystallization can be enhanced by addition of a seed crystal of 26. After 2 crystallizations the mother liquor which was now 85.4 and has a dry weight of 8.7 g. This material was dissolved in 100 ml of 90/10 hexane/ethyl acetate and 10 ml of pure ethyl acetate at 40 C. Pure 25 can be isolated by seeding this solution with a seed crystal 25 of 25 after storing it overnight at 0 C.
~t o S°t 8 ~1.~ o ok (3a,4a,5a) 3-Hutyl-3-ethyl-4,8-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (27) In a _25 ml -round _bottomed_ flask, 1 g of 26 ( 2.5 mmoles) and 10 ml methylene chloride were cooled to - 78 °C
with stirring. Next 0.7 ml of boron tribromide(7.5 mmole) was added via syringe. The reaction was allowed to slowly warm to room temperature and stirred for 6 h.
The reaction was then diluted with 50 ml methylene chloride and washed with saturated NaCI and then water. The organic layer was dried over magnesium sulfate. The product (0.88g) 27 was characterized by NMR and mass spectra.
Example 21 General Alkylation of phenol 27 A 25 ml flask was charged with 0.15 g of 27(0.38 mmole), 5 ml anhydrous DI~', 54 mg of potassium carbonate(0.38 mmole) and 140 mg ethyl iodide (0.9 mmole). The reaction was stirred at room temperature ,overnight. The reaction was diluted with 50 ml ethyl ether and washed with water (25 ml) then 5~ NaOH (20 ml) and then sat. NaCl. After stripping off the solvent the ethoxylated product 28 was obtained in high yield.
The product was characterized by NNgt and mass spectra.
This same procedure was used to prepare products listed in table 1 from the corresponding iodides or bromides.
For higher boiling alkyl iodides and bromides only one equivalent of the alkyl halide was used.

Ro \ : S ,' i ~,, off Table 1 Compound No. R

26 Me 28 Et 29 hexyl 30 Ac 31 (CH2)6-N-pthalimide (3a,4a,5a) 3-Hutyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (37) and (3a,4b,5b) 3-Hutyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-IS 1,1-dioxide (38) Step 1. Preparation of 2-chloro-5-nitrodiphenylmethane cv (32) 1 Nvi Procedure adapted from reference :Synthesis -Stuttgart 9 770-772 (1986) Olah G. Et al Under nitrogen, a 3 neck flask was charged with 45 g (0.172 mole ) of 2-chloro-5-nitrobenzophenone in 345 ml methylene chloride and the solution was cooled to ice/water temperature. By means of an additional funnel, 150 g( 0.172 mole) of trifluoromethane sulfonic acid in 345 ml methylene chloride was added slowly.
Next 30 g of triethylsilane (0.172 mole) in 345 ml methylene chloride was added dropwise to the chilled solution. Both addition steps( trifluoromethane sulfonic acid and_triethylsilane)were repeated. After the additions were completed the reaction was allowed to slowly warm up to room temperature and stirred for 12 h under nitrogen. The reaction. mixture was then poured into a chilled stirred solution of 1600 ml of saturated sodium bicarbonate. Gas evolution occurred.
Poured into a 4 liter separatory funnel and separated layers.. The methylene chloride layer was isolated and (83 WO 98/40375 PCTlUS98/03792 combined with two 500 ml methylene chloride extractions of the aqueous layer. The methylene chloride solution was dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to give 39 g product. Structure 32 was confirmed by mass spectra and proton and carbon NMR.
~~r G -v Step 2. Preparation of 2-((2-benzyl-4-~iN
nitropheaylthio)methyl)-2-ethylhexanal (33) (33, The 2-chloro-5-nitrodiphenylmethane product 32 (40 g, 0.156 mole) from above was placed in a 2 liter 2 neck flask with water condenser. Next 150 ml DMSO and 7.18 g (0.156 mole) of lithium sulfide was added and the solution was stirred at 75 °C for 12 h. The reaction was cooled to room temperature and then 51.7 g of mesylate IV was added in 90 ml DMSO. The reaction mixture was heated to 80 °C under nitrogen. After 12 h monitored by TLC and added more mysylate if necessary.
Continued the reaction until the reaction was completed. Next the reaction mixture was slowly poured into a 1900 ml of 5~ acetic aqueous solution with stirring, extracted with 4 X 700 ml of ether, and dried over MgS04. After removal of ether, 82.7 g of product was isolated. The material can be further purified by silica gel chromatography using 95~ hexane and 5 %
ethyl acetate. If pure mysylate was used in this step there was no need for further purification. The product 33 was characterized by mass spectra and NMR.
Step 3. Oxidation of the vitro product 33 to the sulfoae 2-((2-benzyl-4-aitrophenylsulfonyl)methyl)-2-ethylhexanal (34) The procedure used to oxidize the sulfide 33 to the sulfone 34 has been previously described.
S°L sk o ~ C-E
ON
t ~ ~ N C34 1~~-~~i' r,.,i ... ' ~E
ik~~Ju Step 4. Reduction of 34 to 2-((2-benzyl-4-hydroxyaminophenylsulfonyl)methyl)-2-ethylhexanal (35) A 15 g sample of 34 was dissolved in 230 ml of ethanol and placed in a 500 ml rb flask under nitrogen. Next 1.5 g of 10 wt.% Pd/C was added and hydrogen gas was bubbled through the solution at room temperature until the nitro substrate 34 was consumed. The reaction could be readily monitored by silica gel TLC using 80/20 to hexane/EtOAc. Product 35 was isolated by filtering off the Pd/C and then stripping off the EtOH solvent. The product was characterized by Nl~t and mass spectra.
Step 5. Preparation of the 2-((2-benzyl-4-N,O-di-(t-butoxy-carbonyl)hydroxyaminophenylsulfonyl)methyl)-2 5~~
a thylhexanal ( 3 6 ) . a°c ° ~ ° ~ Et cl~c o- ~' A 13.35 g sample of 35 (0.0344 mole) in 40 ml of dry '~
THF was stirred in a 250 ml round bottomed flask. Next added 7.52 g (0.0344 mole) of di-t-butyl dicarbonate in 7 ml THF. Heated at 60 °C overnight. Striped off THF
and redissolved in methylene chloride. Extracted with 1 % HCl; and then 5% sodium bicarbonate.
The product was further purified by column chromatography using 90/IO hexane/ethyl acetate and then 70/30 hexane/ethyl acetate. The product 36 was obtained (4.12 g) which appeared to be mainly the di-( t-butoxycarbonyl ) derivatives by proton NIA. ~~S°~ 8;,~
Ii~N~ ~'~E
Step 6. (3a,4a,5a) 3-Hutyl-3-ethyl-4-hydroxy-7-- (31 - 30 hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine I,1-dioxide (37) and (3a,4b,5b) 3-Hutyl-3-ethyl-4-hy~oxy-7-hYdroxyamino-5-phenyl-2,~3, 4, 5- -. __ sat tetrahydrobenzothiepine-1,1-dioxide (38)ItoNk ~
oc~ (3s~
A 250m1 3-neck round bottomed flask was charged with 4 g of 36 (6.8 mmoles), and 100 ml of anhydrous THF and cooled to -78 °C under a nitrogen atmosphere. Slowly add 2,.29 g potassium tent-butoxide(20.4 mmoles) with ~ ~5 stirring and maintaining a -78 °C reaction te.-nperature.
After 1 h at -78 °C the addition of base was completed and the temperature was brought to -10 °C by means of a ice/salt bath. After 3 h at -10 °C, only trace 36 remained by TLC. Next add 35 ml of deionized water to the reaction mixture at -10 °C and stirred for 5 min.
Striped off most of the THF and added to separatory funnel and extracted with ether until all of the organic was removed from the water phase. The combined ether phases were washed with saturated NaCl and then dried over sodium sulfate. The only products by TLC and NMR were the two BOC protected isomers of 37 and 38.
The isomers were separated by silica gel chromatography using 85~ hexane and 15 ~ ethyl acetate; BOC-37 (0.71 g) and BOC- 38 (0.78 g).
Next the BOC protecting group was removed by reacting 0.87 g of HOC-38 (1.78 mmoles) with 8.7 ml of 4 M HC1 (34.8 mmoles)in dioxane for 30 min. Next added 4.74 g of sodium acetate (34.8 mmoles) to the reaction mixture and 16.5 ml ether and stirred until clear. After transferring to a separatory funnel extracted with ether and water and then dried the ether layer with sodium sulfate. After removing the ether, 0.665 g of 38 was isolated. Isomer 37 could be obtained in a similar procedure . o s~z ~EE
no"~'~ ° I+( v ( 3q, _ Fxam~le 23 (3a,4a,5a) 3-Butyl-3-ethyl-7-(a-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrcbenzothiepine-1,1-dioxide (40) and (3a,4b,5b) 3-Butyl-3-ethyl-7-(a-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (41) Step 1. 2-((2-Henzyl-4-(n-hexylamino)phenylsulfonyl)methyl)-2-ethylhexanal (39) In a Fischer porter bottle weighed out 0.5 g of 34 (1.2 mmoles) and dissolved in 3.8 ml of ethanol under l$6 nitrogen. Next added 0.1 g of Pd/C and 3.8 ml of hexanal. Seal and pressure to 50 psi of hydrogen gas.
Stirred for 48 h. After filtering off the catalyst and removing the solvent by rotary evaporation 39 was ~ isolated by column chromatography (0.16 g) using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. The product was characterized by N1~ and mass spectra.
,Step 2. (3a,4a,5a) 3-Hutyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (40) and (3a,4b,5b) 3-Hutyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5- p s~z Rq tetrahydrobenzothiepine-l, l-dioxide (41) HeF~''~
IS ~ a 4 C4o A 2-neck, 25 ml round bottomed flask with stir bar was charged with 0.158 g 39 (0.335 mmole) and 5 ml anhydrous THF under nitrogen. Cool to -10 °C by means of a saltwater bath. Slowly add 0.113 g of potassium tert butoxide (0.335 mmole). After 15 min at -10 °C all of the starting material was consumed by TLC and only the two isomers 40 and 41 were observed. Next added 5 ml of chilled 10% HC1 and stirred at -10 °C for 5 min.
Transferred to a separatory funnel and extract with ether. Dried over sodium sulfate. Proton NN~ of the dried product (0.143 g) indicated only the presence of the two isomers 40 and 43. The two isomers were separated by silica gel chromatography using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. 40 ( 53.2 mg): 41(58.9 mg). 5°~
u4' - ~, C 4 ~
Example 24~
v Quateraization of amine substrates 40 and 41 Amine products such as 40 and 41 can be readily alkylated to quaternary salts by reaction with alkyl halides. For example 40 in DMF with 5 equivalents of l ~'1 methyl iodide in the presence of 2.6 dimethyl lutidine produces the dimethylhexylamino quaternary salt.
.~S°y, ...,E ( 42~
~xamnle 25 ou (3a,4b,5b) 3-Hutyl-3-ethyl-4-h~ydroxy-5-(4-iodophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (42) In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d 0.67 g of mercuric triflate were dissolved in 20 ml of dry methylene chloride with stirring. Next 0.34 g of Iodine was added and the solution was stirred at room temperature for 30 h. The reaction was then diluted with 50 ml methylene chloride and washed with 10 ml of 1 M sodium thiosulfate; 10 ml of saturated KI ; and IS dried over sodium sulfate. See Tetrahedron, Vo1.50.
No. I7, pp 5139-5146 (1994) Bachki. F. Et al. Mass spectrum indicated a mixture of 6d , mono iodide 42 and a diiodide adduct. The mixture was separated by column chromatography and 42 was characterized bt NMR and mass Sv spectra. V
'w Et o ~l~
Examble 26 o-(3a,4b,5b) 3-Hutyl-5-(4-carbomethoxyphenyl)-3-ethyl-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (43) A 0.1 g sample of 42 ( 0.212 mmole). 2.5 ml dry methanol, 38 ul triethylamine (0.275 mmole) . 0.3 ml toluene and 37 mg of palladium chloride (0.21 mmole) 3o was charged to a glass lined mini reactor at 300 psi carbon monoxide. The reaction was heated at 100 °C
overnight. The catalyst was filtered and a high yield of product was isolated.
The product was characterized by NMR and mass spectra.
Note the ester functionalized product 43 can be converted to the free acid by hydrolysis.
l~$

Fxamule 27 (3a,4a,5a) 3-Hutyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetzahydrobenzothiepiae-1,1-dioxide (48), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (49) Step 1. 2-Mercapto-5-methoxybenzophenone (50) ~ a ac~t~ (5=
Reaction of 66.2 g of 4-methoxythiophenol with 360 ml l0 of 2.5 N n-butyllithium, 105 g of ~tetramethylethylenediamine and 66.7 g of benzonitrile in 600 ml cyclohexane according to the procedure in WO
93/16055 gave 73.2 g of brown oil which was kugelrohr distilled to remove 4-methoxythiophenol and gave 43.86 g of crude 50 in the pot residue.
Step 2. 2-((2-Henzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal (51) c ~s o ~_~ h~= E<
J
Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g (0.02 mole)of mesylate 1 and 3.2 ml (0.23 mole) of triethylamine in 50 ml of diglyme according to the procedure for the preparation of 2 gave 10.5 g of crude product which was purified by HPLC (5~ ethyl acetate-hexane) to give 1.7 g (22$) of 51.
Step 3. 2-((2-Henzoyl-4-methoxypheaylsulfonyl)methyl)-2-ethyl-hexanal (52) o s°~ B:.
ta; ~ ° ~ Et Cs~~
o r~
A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of methylene chloride was reacted with 2.0 g (6.2 mmoles) ' of 50-60% MCPBA according to the procedure of step 2 of procedure~A in example 18 gave 1.16 g (90$) of 52 as a yellow oil.
Step 4. 2-((2-Henzyl-4-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (53) 0 5°Z
B
i~3 v a EE
1.1 ~°
pq C53, Hydrogenation of 1.1 g of 52 according to the procedure of step 3 of procedure A of example 18 gave 53 as a yellow oil (1.1 g).
Step 5. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (48), and (3a,4b,5b) 3-Hutyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobeazothiepine-1,1-dioxide (49) o srl 6~ ~S°~d., ~'C-E u~c:J~>~_ "Et (~~i, v o « ~,rEg 3 ' cH.
A solution of 1.1 g of 53, , .36 g o~potassium t-butoxide and 25 ml of anhydrous THF was held at reflux for 2 h and worked up as in step 4 of procedure A of example 18 to give 1.07 g of a crude product which was purified by HPLC to give 40 mg (4%) of 48 as crystals, mp 153-154 °C and 90 mg (8%) of 49 as solid, mp 136-140 °C ~ ~s~t lk O
v y 4 l~xam~le 28 v S'?~ ~ C5 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1'-cyclohexane (57) Step 1. 1-(Hydroxymethyl)-cyclohexanecarboxaldehyde (54) To a cold (O~C'mixture of 100 g (0.891 mole) of cyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml of methanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1 h. The reaction mixture was stirred at room temperature over 48 then was evaporated to remove methanol. The reaction mixture was diluted with water and extracted with__methylene chloride. The organic layer was washed with water, brine, and~dried over sodium sulfate and concentrated under vacuum to give 75 g (59.7%) of thick oil. Proton NNgt and mass spectra were consistent with the product.
Step 2. 1-(mesyloxymethyl)cyclohexaaecarboxaldehyde (55) 0 . i~3 C _ S _ c3~~
1 °~ o To a cold (O~C'mixture of alcohol 54 (75 g, 0.54 mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylene chloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 ml of methylene - chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with conc. HC1 and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g (77.8%) of thick oil.
Proton NI~t and mass spectra were consistent with the product. o S
Step 3. 1-((2-Heazoylphenylthio)methyl)cyclohexanecarboxaldehyde (56) A mixture of 69 g (0.303 mole) of 2-mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil. HC1 and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme.
This was purified by silica gel flush column (5% EtOAc:
Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton NMR and mass spectra were consistent with the product.
Step 4. 5-Pheayl-2,3-dihydrospirobeazothiepine-3,1~-cyclohexane ( S7 ) _ _ ~ S
.,_ C 5'?
To a mixture of 6.19 g of zinc dust and 100 ml of dry DME was added TiCl,(I6.8 g, 0.108 mole) . The reaction - 35 mixture was heated to reflux for 2 h. A solution of compound 56 (8.3 g, 0.023 mole) in 50 ml of DME was added dropwise to the reaction mixture in 1 h and the mixture was held at reflux for 18 h. The mixture was lei cooled, poured into water and extracted with ether. The organic layer was washed with water, brine, and dried over sodium sulfate, filtered through celite and concentrated under vacuum. The residue was purified by HPLC (10% EtOAc: Hexane) to give 4.6 g (64%) of white solid, mp 90-91 ~C. Proton and carbon NMR and mass spectra were consistent with the product.
~So1 ° ' ~ c5~~
Exa_mnle 29 '8b-Phenyl-1a,2,3,8b-tetrahydrospiro(benzothiepino[4,5-b]oxirene-2,1'-cyclohexane)-4,4-dioxide (58) To a solution of 57 (4.6 g, 15 mmole) in 50 ml chloroform under nitrogen was added 55% MCPBA (16.5 g, 52.6 mmole) portionwise with spatula. The reaction was held at reflux for 18 h and washed with 10% NaOH(3X), water, brine, and dried over sodium sulfate and concentrated under vacuum to give 5 g of crude product.
This was recrystallized from Hexane/EtOAc to give 4.31 g (81%) of yellow solid, mp 154-155 ~C. Proton and carbon NMR and mass spectra were consistent with the 5°z product. G
Cs~~
Fxam~l a 3 0 ~ 011 tzans-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro spiro(benzothiepine-3,1'-cyclohexane)-1,1-dioxide (59) A mixture of 0.5 g (1.4 mmoles) of 58 , 20 ml of ethano1.10 ml of methylene chloride and 0.4 g of 10%
Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10%,EtOAc-Hexane, 25%
EtOAc-Hexane). The first fraction was 300 mg (60%) as a white solid, mp 99-100 ~C. Proton NMR showed this was a trans isomer. The second fraction gave 200 mg of solid which was impure cis isomer.

SJl l6 0~
Fxam~le 31 p o N
cis-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro spiro(benzothiepine-3,1'-cyclohexane)-l,l-dioxide (60) s To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH,C1,, was added 8 g of 50% NaOH and one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst. The reaction mixture was stirred for ,10 h at room temperature. Twenty g of ice was added to the mixture and the mixture was extracted with CH,Cl=
(3x10 ml) washed with water, brine and dried over MgSO, and concentrated in vacuo to recover O.I5 g of crude product. This was recrystallized from Hexane/EtOAc to give 125 mg of white crystal, mp 209-210 'C . Proton and carbon NMR and mass spectra were consistent with the product. S Bw 5 C~ ~ ', Et ~ r~ ~t ~' 6 2 ~u (6!, ~amr,~le 32 (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (61), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (62) To a solution of 0.5 g (1.47 mmole) of compound 47 in 5 ml of anhydrous THF was added 0.17 g (1.47 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred at room temperature for 18 h and quenched with 10 ml of 10% HC1. The organic was extracted into methylene chloride. The methylene chloride extract was _ dried over magnesium sulfate and concentrated in vacuo.
The residue was purified by HPLC (2% EtOAc-hexane) to give 47 mg of 61 in the second fraction and 38 mg of 62 in the third fraction. Proton NMR~and mass spectra were consistent with the assigned structures.
S0~
Fxam~ 1 a 3 3 ~ g,~ ~ 5~' g,, n,, E~
~~'' oh 6 3~
C~93 ~~~) (3a,4a,5a) 3-Hutyl-3ethyl-4-hydroxy-7-amino-5-pheayl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (63) and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(64) An autoclave Was charged with 200 mg of 37 in 40 cc ethanol and .02 g 10 % Pd/C. After purging with nitrogen the clave was charged with 100 psi hydrogen and heated to 55 C. The reaction was monitored by TLC
and mass spec and allowed to proceed until all of 37 was consumed. After the reaction was complete the catalyst was filtered and the solvent was removed in vacuo and the only observable product was amine 63.
This same procedure was used to produce 64 from 38.
SJ
~5~~ g~ p ~ t 8 D
'''EC
~rco j /~3co ''ON
Example 34 ~ G~ (b5> U
ocu (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (65), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (66).
Alkylation of e-methoxyphenol with 3-methoxybenzyl chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3'-methoxybenzyl)phenol in 35% yield. This material was converted to compound 65, mp 138.5-141.5 °C, and compound 66, mp 115.5-117.5 °C, by the procedure similar to that in Example 18 method B.
~,,xample 35 (3a,4a,5a) ~3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'- -(trifluoromethyl)phenyl)-2,3.4,5-tetrahydrobenzothiepine-1,1-dioxide (67), and~~
(3a,4b;5b) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5~-(3'-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (68).
s°t 6 V e~, ~ ~., E~
c~~c o ~ ~~.EE 3 0 F c ~ a a (6'l~ ~ o ~
I q'~ 3 ~3' C& ~~

Alkylation of 4-methoxyphenol with 3-(trifluoromethyl)benzyl chloride according to the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy-2-(3'-(trifluoromethyl)benzyl)phenol. This material was converted to compound 67, mp 226.5-228 °C, and compound 68, mp 188-190°C, byu the procedure similar to that in Example 18 method B.s~
s~i 8c, v 3_~r Ex~ple 36~~
'' l0 (3a,4a,5a) 3-B ty -3-ethyl-5-(4'-.fluorophenyl)-4 Ihydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (69), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (70).
IS
Alkylation of 4-methoxyphenol with 4-fluorobenzyl chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methoxy-2-(4'-fluorobenzyl)phenol. This material was converted to 20 compound 69 and compound 70 by the procedure similar to that in Example 18 method B. v i°t cJ 5''z c o'~ B..
y~'~ ~ Y_ Example 37 F ° °H (-~11~ F
(3a,4a,5a) 3-Butyl-3-ethyl-5-(3'-fluorophenyl)-4-25 hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (71), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(3'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (72).
30 Alkylation of 4-methoxyphenol with 3-fluorobenzyl chloride according to the procedure described in J.
- Chem. Soc,.2431 (1958) gave 4-methoxy-2-(3'-- fluorobenzjrl)phenol. This material was converted to compound 71 and compound 72 by the~procedure similar to 35 that in Example 18 method B.
~s~c 8~ o B4 Exams 1 a 3 8 N~ v \ '~~ ~ Et ~\ 'c, F & c3 ~ F d ~''ou c 3) ~ C-~ ~-~
(AS

(3a,4a,5a) 3-Butyl-3-ethyl-5-(2'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (73), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(2'-fluorophenyl)-4-hydroxy-7-methoxy-2,3.4.5-tetrahydrobenzothiepine-1,1-dioxide (74).
Alkylation of 4-methoxyphenol with 2-fluorobenzyl chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methoxy-2-(2'-fluorobenzyl)phenol. This material was converted to . compound 73 and compound 74 by the procedure similar to s~~ S°1 Ci,..
that in Example 18 method B. ~ ~ Et'~ pr ~ , "~
8r v 01-~
~'xam~le 39 V a~~°~ ~'!S~ ~o~N x-76 (3a,4a,5a) 3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3'- 3 methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (75), and (3a,4b,5b) 3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (76).
Alkylation of 4-bromophenol with 3-methoxybenzyl chloride according to the procedure described in J.
Chem. Soc. 2431 (1958) gave 4-bromo-2-(3'-methoxybenzyl)phenol. This material was converted to compound 75, mp 97-101.5 °C, and compound 76, mp 102-106 °C, by the procedure similar to that in Example 18 G O
method B . ~~ 5 i g,, gxamDla 40 ° 6 F F
(3a,4a,5a) 3-Butyl-3-ethyl-7-fluoro-5-(4'-fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (77), and (3a,4b,5b) 3-Butyl-3-ethyl-7-fluoro-5-(4'-fluorophenyl)-4-hydroxy-2,3,4,5- .
tetrahydrobenzothiepine-1.1-dioxide (78).
Alkylation of 4-fluorophenol with 4-fluorobenzyl chloride according to the procedure described in J.
tq6 Chem. Soc, 2431 (1958) gave 4-fluoro-2-(4'-fluorobenzyl)phenol. This material was converted to compound 77, mp 228-230 °C, and compound 78, mp 134.5-139 °C, by the proced vre similar to that in Example 18 me thod B . ~ L B,, -F ''' Et F '' Example 41.' ~ c~~ ~~q' ~ ot~4 ~$0~
'~3 °'~3 (3a,4a,~5a) 3-Butyl-3-ethyl-7-fluoro-4-hydroxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (79), and (3a,4b,5b) 3-Butyl-3-ethyl-7-fluoro-40hydroxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (80).
Alkylation of 4-fluorophenol with 3-methoxybenzyl chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-fluoro-2-(3'-methoxybenzyl)phenol. This material was converted to compound 79, as a solid and compound 80, mp 153-155 °C, by the procedure similar to that in Example 18 method L n g . So vL
(~(~G O icy Example 42 a 1.~
r=
(3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (81).
A mixture of 0.68 (1.66 mmol) of compound 77, 0.2 g (5 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at room temperature for I6 days. The reaction mixture was dilute with ether and washed with water and brine and dried over MoSO,. The ether . solution was concentrated in vacuo. The residue was purified by HPLC (20% ethyl acetate in hexanes). The first fraction was impure (3a,4a,5a) 3-butyl-3-ethyl-4-hydroxy-7-methylthio-5-(4'-fluorophenyl)-2,3,4',5-tetrahydrobenzothiepine-l,l-dioxide. The second fraction was compound 81, mp 185-186.5 °C.

a W .n EE
~N
a rt Examflle 43 (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-flu rophenyl)-4-hydroxy-7-(1-pyrrolidinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (82).
A mixture of 0.53 g (1.30 mmol) of compound 78 and S ml of pyrrolidine was held at reflux for 1 h. The reaction mixture was diluted with ether and washed with water and brine and dried over MaSO,. The ether solution was concentrated in vacuo. The residue was crystallized from ether-hexanes to give comipound 82, mp s~l 174.5-177 °C.
c~~ ~~4> 3 ~ bra CyS
x (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4- ~,,i 8~
hydroxy-7- (1-morpholinyl) -2, 3, 4, 5- ~N.~°~ ,'''EE
tetrahydrobenzothiepine-1,1-dioxide (83). J '' ~~3) r A mixture of 0.4 g (0.98 mmol) of compound 78 and 5.0 g (56 mmol) of morpholine was held at reflux for 2 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over MaSO,. The ether solution was concentrated in vacuo. The residue was recrystallized from ether-hexanes to give compound 83, mp 176.5-187.5 °C.
~xam~le 45 (3a,4a,5a) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (84), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (85).
Alkylation of 4-methylphenol with 4-fluorobenzyl~
chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methyl-2-(4'-fluorobenzyl)phenol). This material was converted to J9a compound 84 and compound 85 by the rocedure similar to that in Example 18 method u.'o ' ~~,E~ ~o E~
ou Exampla 46 e!4 (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-(4'- oN
- hydroxyphenyl)-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (86), and (3a,4b,5b) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'-hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-1~1 dioxide ( 87 ) .
To a solution of 0.52 (1.2 mmol) of compound 66 in 20 ml of methylene chloride was added 1.7 g (6.78 mmol) of born tribromide. The reaction mixture was cooled to -IS 78 °C and was stirred for 4 min. An additional 0.3 ml of boron tribromide was added to the reaction mixture and the reaction mixture was stirred at -78 °C for 1 h and quenced with 2 N HCl. The organic was extracted into ether. The ether layer was washed with brine, 20 dried over MaSO,, and concentrated in vacuo. The residue (0.48 g) was purified by HPLC (30~ ethyl acetate in hexanes). The first fraction was 0.11 g of compound 86 as a white solid, mp 17I.5-173 °C. The second fraction was crystallized from chloroform to 25 give 0.04 g of compound 87 as a white solid, mp 264 °C
(dec) .
O S t 13:
nv~ "~CE
Example 47 ~ ~ « ~$$) (3a,4b,5b) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'-30 fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (88).
Reaction of compound 70 with excess boron tribromide at room. temperature and worked up as.in Example ;46 gave 35 compound 88 after an HPLC purification.
Sol example 48 B4 Coq o c~
r t ~l °I

(3a,4b.5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-(1-azetidinyl)-2,3,4.5-tetrahydrobenzothiepine-1,1-dioxide (89).
A mixture of 0.20 g (0.49 mmol) of compound 78, and 2.0 g (35 mmol) of aztidine was held at reflux for 3 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over MgS04. The ether solution was concentrated on a steam bath. The separated crystals were filtered to ive 0.136 g of 89 as risms, mp 196.5-199.5 °C.
g o ~'z Bu ~ s°z ' 9w ,«,Ef ~t3cs .,Ct Example 49 3 Clo~ ~ ~'1 ~'( ~' V ~~j ock (3a,4a,5a) 3-Butyl-3-et~yl-5-(3'-methoxypheny~)-4->j hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1.1-dioxide (90). (3a.4b,5b) 3-Butyl-3-ethyl-5-(3'-methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (91).
'0 A mixture of 0.4 g (0.95 mmol) of compound 79, 0.08 g (1.14 mmol) of sodium methanethiolate and I5 ml of anhydrous DMF was stirred at 60 °C for 2 h. An additional 1.4 mmol of sodium methanethiolate was added to the reaction mixture and the mixture was stirred at 25 60 °C for an additional 2 h. The reaction mixture was triturated with 100 ml of water and extracted methylene chloride. The methylene chloride water mixture was filtered through Celite and the methylene chloride , layer was dried over M9S0, and concentrated in vacuo.
30 The first fraction (0.1 g) was compound 90, mp 117-121 °C. The second fraction (0.16 g) was compound 91, mp 68-76-.oC:
~Q O

Example 50 Preparation of polyethyleneglycol functionalized benzothiepine 8.
Ho ocH3 i ( ,,.~
/ \
..
..._ _.._ = 'OH
phf',. S~ ~\--__..__ HO''~
No . 141 '~.Et No .

A 50 ml rb flash under a nitrogen atmosphere was _ charged with 0.54 g of M-Tres-5000 (Polyethyieneglycol ,1.0 1 Tresylate [methoxy-PEG-Tres,MW 5000] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway. SW, Huntsville, Alabama 35801). 0.055 g Compound No. 136, 0.326 C,CO, and 2cc anhydrous acetonitrile. The reaction was stirred at 30 C for 5 days and then the solution was filtered to remove salts. Next, the acetonitrile was removed under vacuum and the product was dissolved in THF and then precipitated by addition of hexane. The polymer precipitate was isolate by ,filtration from the solvent mixture (THF/hexane). This precipitation procedure was continued until no Compound No. 136 was detected in the precipitated product (by TLC Si02). Next, the polymer precipitate was dissolved in water and filtered and the water soluble polymer was dialyzed for 48 hours through a cellulose dialysis tube (spectrum~ 7 ,45 mm x 0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried. The NMR was consistent with the desired product A and gel permeation chromatography indicated the presence of a 4500 MW polymer and also verified that no free Compound No. 136 was present. This material was active in the IBAT in vitro cell assay.
1d ~

Examp 1 a ~1 Preparation of Compound 140 . ~ nOH ~~~'~. O
/ ,,~ HO1~" S~
\ ~ .il \ / ...~ \
i \ ~.
O-polyethyleneglycol-O
~2 No. 140 O~S ...pH

\

H

H2 No. 111 A 2-necked 50 ml round bottom Flask was charged with 0.428 of Tres-3400 (Polyethyleneglycol Tresylate [Tres-PEG-Tres,MW 3400) purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.1 potassium carbonate, O.100g of Compound No.
111 and 5 ml anhydrous DMF. Stir for 6 days~at 27 °C.
TLC indicated the disappearance of the starting Compound No. 111. The solution waS transferred to a separatory funnel and diluted with 50 cc methylene chloride and then extracted with water. The organic layer was evaporated to dzyness by means of a rotary evaporator. Dry wgt. 0.4875 g. Next, the polymer was dissolved in water and then dialyzed for 48 hours at 40 °C through a cellulose dialysis tube (spectrum~ 7 ,45mm x 0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried 0.341 g). NIA was consistent with the desired product B.
Example 52 0~~ ~ 0 v ~
~'ox No. 134 A 10 cc vial was charged with 0.21 g of Compound No.
136 (0.5mmoles), 0.17g (1.3 mmoles)potassium carbonate, 0.6g (1.5 mmoles) of 1,2-bis-(2-iodoethoxy)-ethane and 10 cc DMF. The reaction was stirred for 4 days at room temperature and then worked up by washing with ether/water. The ether layer was stripped to dryness and the desired product Compound No. 134 was isolated on a silica gel column using 80/20 hexane ethyl acetate:
20 ~-Example 53 o=s ..~oH
~ ~"'"~ ~ I Hpn.,.
' \ /~o ~'~O ~o s ~

\ .
No. I12 Example 54 pig ...,~uIOH
... .. ..
/ \
i \
No. 113 2o S

A two necked 25 ml round bottom Flask was charged with 0.58 (1.24mmoles) of 69462, 13 mls of anhydrous DMF, 0.0558 of 60% NaH dispersion and 0.2308 (0.62 mmoles) of 1,2-Bis [2-iodoethoxylethane) at 10 °C under nitogen. Next, the reaction was slowly heated to 40 °C. After 14 hours all of the Compound No. 113 was consumed and the reaction was cooled to room temperature and extracted with ether/water. The ether layer was evaporated to dryness and then chromatographed on Silicage (80/20 ethyl acetate/hexane). Isolated Compound No. I12 (0.28 g) was characterized by NMR and mass spec.
Example 55 o,.°
/ \
~OH
\ / 0~ 0 ~S~
i ~OH
\ / No . 13 5 0' S O , H ~ ....1 ~'bH
' No. 136 a.o ~

In a 50 ml round bottom Flask, add 0.78 (1.8 mmoles) of Compound No. 136, 0.6218 of potassium carbonate, 6 ml DMF, and 0.338 of 1,2-Bis [2-iodoethoxylethane]. Stir _ 5 at 40 °C under nitrogen for 12 hours. The workup and isolation was the same procedure for Compound No. 112.
Examples 56 and 57 (Compound Nos 131 and 137) The compositions of these compounds are shown in Table 3.
The same procedure as for Example 55 except appropriate benzothiepine was used.
Example 58 (Compound No. 139) The composition of this compound is shown in Table 3.
Same procedure as for Example 55 with appropriate benzothiepine 1,6 diiodohexane was used instead of 1,2-Bis [2-iodoethoxylethane].
Example 59 (Compound No. 10~) _ .~ ..
O S ,~~'OH o~s/ ..~uOH
ii O
\ ....~~ /
......
I \t w __ _d. . ,H No .
lol This compound is prepared by condensing the 7-NH=
benzothiepine with the 1,12-dodecane dicarboxylic acid or acid halide.
~v'?

I i Example 60 fCom~ound No. 104) a ."npFi . y '' ~'~ ~ No . 10 4 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII.
Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme 5). Reduction of the sulfone-aldehyde XXV formaldehyde and 100 psi hydrogen and 55 C for 12 hours catalyzed by palladium on carbon in the same reaction vessel yields the substituted dimethylamine derivative XXVIII. Cyclization of XXVII
with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention Compound No. 104.

Scheme 6 ~
~: N
~~ N1. f 1 l C- Il' C ~ N
~:
/ /
N ~' \
N K~, IY
XXI V N
IN~ ~ TNf ~ 1 1 \\S/ Itt \\ // !t1 / ~~ / ~2 ..11 ~~~~~1 \ \
~,~ ~H ~~N 111 H P~ H Ph xx~ xc xx~ x~
Example 61 .S ..,~IIpH
/ ...~y \' I /
1.
~ ~ No. 102 A 1 oz. Fisher-porter bottle was charged with 0.14 g (0.34 mmoles) of 70112, 0.97 gms (.6.8 mmoles) of methyl - iodide, and 7 ml of anhydrous acetonitrile. Heat to 50 °C for 4 days. The goat. Salt Compound No. 192 was isolated by concentrating to 1 cc acetonitrile and then precipitating with diethyl ether.
;LSO

Example 62 o 's~
,.l OH
N
No. 125 A 0.1 g (0.159 mmoles) sample of Compound No. 134 was dissolved in 15 ml of anhydrous acetonitrile in a Fischer-porter bottle and then trimethylamine was bubbled through the solution for 5 minutes at 0 °C and then capped and warmed to room temperature. The reaction was stirred overnight and the desired product was isolated by removing solvent by rotary evaporation.
Example 63 (Compound No. 2951 //.
~~~DH
_.. w ~o ~ ~
__. ._ H2 No. 295 ~~1 rr -- ,"OOH
\ ..~~r i \ H
No. 113 Sodium Hydride 60~ (11 mg, 0.27 mmoles) in 1 cc of acetonitrile at 0 °C was reacted with 0.248 mmoles (.10 g) of Compound No. 54 in 2.5cc of acetonitrile at 0 °C.
Next, 0.(9808 2.48 mmoles) of 1,2-Bis [2-iodoethoxylethaneJ. After warming to room temperature, stir for 14 hours. The product was isolated by column chromatography.
Example 64 (Compound No. 286) o _ ,~o PhCH2 No. 286 Following a procedure similar to the one described in Example 86, infra (see Compound No. 118), the title compound was prepared and purified as a colorless 24 solid; mp 180-181 °C; 1H NI~t (CHC1~) S 0.85 (t, J = 6 Hz, 3H_, 0.92 (t, J = 6 Hz, 3H), 1.24-1.42 (m, 2H), 1.46-1.56 (m, 1H), 1.64-1.80 (m, 1H), 2.24-2.38 (m, 1H), 3.15 (AB, J", = 15 Hz, Ov = 42 Hz, 2H), 4.20 (d, J
'~ 1~.

- 8 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.46 (s, 1H), 6.6E (s, 1H), 7.29-7.51 (m, lOH), 7.74 (d, J = 8 Hz, 1H), 8.06 (d, J = 8 Hz, 1H). FARMS m/z 494 (M+H), HRMS
calcd for (M+H) 494.2001, found 494.1993. Anal. Calcd.
for C"H"NOsS: C, 68.13; H, 6.33; N, 2.84. Found: C, 68.19; H, 6.56; N, 2.74.
~~3 Example 65 fCom~ound No. 2871 O~S/
HZ .~OH
No. 287 Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 245-246 °C, 1H NMR (CDC1,) 8 0.84 (t, J = 6 Hz, 3H), 0.92 (t, J = 6 Hz, 3H), 1.28, (d, J = 8 Hz, 1H), 1.32-1.42 (m, 1H), 1.48-1.60 (m, 1H), 1.64-1.80 (m, 1H), 2.20-2.36 (m, 1H), 3.09 (AB, J", = 15 Hz, w =
42 Hz, 2H), 3.97 (bs, 2H), 4.15 (d, J = 8 Hz, 1H), 5.49 (s, 1H), 5.95 (s, 1H), 6.54 (d, J = 7 Hz, 1H), 7.29-7.53 (m, 5H), 7.88 (d, J = 8 Hz, 1H); ESMS 366 (M+Li).
Anal. Calcd. for C~oHssNO~S: C, 66.82; H, 7.01; N. 3.90.
Found: C, 66.54; H, 7.20; N, 3.69.
Example 66 (Compound No. 2881 o\~
H ~ i ~~'bH
i No. 288 ~1~

Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a colorless solid: mp 185-186°C; 1H NMR (CDC1,) 81.12 (s, 3H), 1.49 (s, 3H), 3.00 (d, J = 15 Hz, 1H), 3.28 (d, J
- 15 Hz, IH), 4.00 (s, 1H), 5.30 (s, 1H), 5.51 (s, 1H), 5.97 (s, 1H), 6.56 (dd, J = 2.1, 8.4 Hz, 1H). 7.31-7.52 (m, 5H), 7.89 (d, J = 8.4 Hz, 1H). MS (FAH+) (M+H) m/z 332.
Example 67 (Compound No. 289) o~~ P
I /
2.
bH
No. 289 Following a procedure similar to the one described in Example 89 (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a white solid: mp 205-205 °C; iH NMR (CDC1~) 8 0.80-0.95 (m, 6H), 1.10-1.70 (m, 7H), 2.15 (m, 1H), 3.02 (d, J = 15.3 Hz, 2H), 3.15 (d; J = 15.1 Hz, 2H); 3.96 (s,' br, 2H), 4.14 (d, J~ = 7. 8 Hz, 1H) , 5.51 (s, 1H) , 5.94 (d, J =
2.2, IH), 6.54 (dd, J = 8.5, 2.2 Hz, 1H), 7.28-7.50 (m, 6H), 7.87 (d, J = 8.5 Hz, 1H). MS (FAB): m/z 388 (M+H).
Examnle68 (Compound No. 2901 ~l5 O~S
W \
H
~OH
r No. 290 ~ Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp = 96-98 °C, 1H NMR (CDC1~) b 0.92 (t, J = ?
Hz, 6H), 1.03-1.70 (m, 11H), 2.21 (t, J = 8 Hz, 1H), 3.09 (AB, J", = 18 Hz, w = 38 Hz, 2H), 3.96 (bs, 2H), 4.14 (d, J = 7 Hz, 1H), 5.51 (s, 1H), 5.94 (s, 1H), 6.56 (d, J = 9 Hz, 1H), 7.41-7.53 (m, 6H), 7.87 (d, J =
8 Hz, 1H); FARMS m/z 416 (M+H).
Example 69 o~si O W \
PhCH20~N
H ~~OH
No. 291 Follo~ring a procedure similar to the one described in Example 86, infra (see Compound~No. 118), the title compound was prepared and purified as a colorless solid: iH NMR (CDC1,) S 0.91 (t, J = 7 Hz, 6H), 1.02-1.52 (m, I1H), 1.60-1.70 (m, 1H), 2.23 (t, J = 8 Hz, ~lL

1H), 3.12 (AB, Ju = 18 Hz, w = 36 Hz, 2H), 4.18 (d, J
- 7 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.43 (s, 1H), 6.65 (s, 1H), 7.29-7.52 (m, lOH), 7.74 (d, J = 9 Hz, 1H), 8.03 (d, J = 8 Hz, 1H); ESMS m/z 556 (M+Li).
'x.11 Examine 70 (Compound No. 292) H / V~
~~bH
No. 292 Following a procedure similar tb the one descried in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp = 111-112.5°C, 1H NMR (CDC1~) b 0.90 (t, J = 8 Hz, 6H), 1.03-1.50 (m, lOH), 1.55-1.70 (m, 2H), 2.18 (t, J = 12 Hz, 2H) , 3 .07 (AB, J,,, = 15 Hz, Ov = 45 Hz, 2H), 4.09 (bs, 2H), 5.49 (s, 1H), 5.91 (s, 1H), 6.55 (d, J = 9 Hz, 1H), 7.10 (t, J = 7 Hz, 2H), 7.46 (t, J =
6 Hz, 2H), 7.87 (d, J = 9 Hz, 1H).
Example 71 (Compound No. 293) w w PhCH
~bH
No. 293 During the preparation of Compound No. 290 from Compound No. 291 using BBr,, the title compound was ~ 1~

isolated: 'H NMR (CDC1~) 8 0.85 (t, J = 6 Hz, 6H), 0.98-1.60 (m, lOH), 1.50-1.66 (m, 2H), 2.16 (t, J = 8 Hz, 1H), 3.04 (AB, J", = 15 Hz, w = 41 Hz, 2H), 4.08 (s, 1H), 4.12 (s, 1H),.5.44 (s, 1H), 5.84 (s, 1H), 6.42 (d, J = 9 Hz, 1H), 7.12 (d, J = 8 Hz, 2H), 7.16-7.26 (m, lOH), 7.83 (d, J = 8 Hz, 1H); ESMS m/z 512 (M+Li).
Example 72 (Comr~ound No 2941 Following a procedure similar to the one described in Example 60 (Compound No. 104), the title compound was prepared and purified as a colorless solid: 1H NMR
(CDC1~) 8 0.90 (t, J = 6 Hz, 6H), 1.05-1.54 (m, 9H), 1.60-1.70 (m, 1H), 2.24 (t, J = 8 Hz, 1H), 2.80 (s, 6H), 3.05 (AB, J,,, = 15 Hz, w = 42 Hz, 2H), 4.05-4.18 (m, 2H), 5.53 (s, 1H), 5.93 (s, 1H), 6.94 (d, J = 9 Hz, 1H), 7.27-7.42 (m, 4H), 7.45 (d, J = 8 Hz, 2H), 7.87 (d, J - 9 Hz, 1H); ESMS m/z 444 (M+H).
Structures of the compounds of Examples 33 to 72 are shown in Tables 3 and 3A.
Examples 73-79, 87, 88 and 91-10 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, compounds were prepared having the structures set forth in Table 3.
The starting materials illustrated in the reaction schemes shown above were varied in accordance with principles of organic synthesis well known to the art to introduce the'indicated substituents in the 4- and 5- positions (R', R', R', R') and in the indicated position on the benzo ring (R").
~~9 Structures of the the compounds produced in Examples 73-102 are set forth in Tables 3 and 3A.
Examples 80-84 Preparation of 115, 116, 111, 113 Preparation of 4-chloro-3-[4-methoxy-phenylmethyl~-nitrobenzene.
In a 500 ml 2-necked rb flask weigh out 68.3 gms phosphorus pentachloride (0.328 mole 1.1 eq). Add 50 mls chlorobenzene. Slowly add 60 gms 2-chloro-5 nitrobenzoic acid (0.298 mole). Stir at room temp overnight under N2 then heat 1 hr at 50C.
Remove chlorobenzene by high vacuum. Wash residue with hexane. Dry wt=55.5 gms.
In the same rb flask, dissolve acid chloride (55.5 g 0.25 mole) from above with 100 mls anisole (about 3.4 eq). Chill solution with ice bath while purging with N2. Slowly add 40.38 aluminum chloride (1.2 eq 0.3 mole). Stir under N~ for 24 hrs.
After 24 hrs, the solution was poured into 300 mls 1N HC1 soln. (cold). Stir this for 15 min. Extract several times with diethyl ether. Extract organic layer once with 2~ aqueous NaOH then twice with water.
Dry organic layer with MgS04, dry on vac line. Solid is washed well with ether and then ethanol before drying. Wt=34.578 (mixture of meta, ortho and para).
Elemental theory found C 57.65 57.45 H 3.46 5.51 N 4.8 4.8 C1 12.15 12.16 2 ~o With the next step of the reduction of the ketone with trifluoromethane sulfonic aid and triethyl silane, crystallization with ethyl acetate/hexane affords pure 4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene.
4-Chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene was then reacted as specified in the synthesis of 117 and 118 from 2-chloro-4-nitrophenylmethane. From these procedures 115 and 116 can be synthesized. Compounds 111 and 113 can be synthesized from the procedure used to prepare compound 121.
Compound 114 can be prepared by reaction of 116 with ethyl mercaptan and aluminum trichloride.
Examples 85 and 86 Preparation of 117 and 118 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII.
Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme 5).
The sulfone-aldehyde (31.8 g) was dissolved in ethanol/toluene and placed in a parr reactor with 100 ml toluene and 100 ml of ethanol and 3.2 g of 10% Pd/C
and heated to 55 C and 100 psi of hydrogen gas for 14 hours. The reaction was then filtered to remove the catalyst. The amine product (.076 moles, 29.5 g) from this reaction was then reacted with benzyl chloroformate (27.4g) in toluene in the presence of 35 g of potassium carbonate and stirred at room ~a-l i temperature overnight. After work up by extraction with water, the CBZ protected amine product was further purified by precipitation from toluene/hexane.
The CBZ protected amine product was then reacted with 3 equivalents of potassium t-butoxide in THF at O
C to yield compounds 117 and 118 which were separated by silica gel column chromatography.
Examples 89 and 90 Preparation of 121 or 122 Compound 118 (.013 moles, 6.79g) is dissolved in 135 ml of dry chloroform and cooled to -78 C, next 1.85 ml of boron tribromide (4.9 g) was added and the reaction is allowed to warm to room temperature.
Reaction is complete after 1.5 hours. The reaction is quenched by addition of 10$ potassium carbonate at 0 C
and extract with ether. Removal of ether yields compound 121. A similar procedure can be used to produce 122 from 117.
Examples 93-96 Compounds 126, 127, 128 and 129 as set forth in Table 3 were prepared substantially in the manner described above for compounds 115, 116, 111 and 113, respectively, except that fluorobenzene was used as a starting material in place of anisole.
~~:2 Specific compounds (x102-111,113-130,132-134,136,138,142-144,262-296) ,,,,~ R
(g")q ~ ~ ~ 4' ~ R2 ~~~~, R3 Rs. Rs R
C=, . Ri RZ R3 R~ RS R6 (R=) a Dc.

61 302 . Et- n-8u- HO- H- Ph- H' I-, ?-. : ( C3 ~ 3N+_ 73 103 n-3u- Et- FO- F:- Ph- F.- I-, ?-{Ci:3 ) 3N~_ 60 104 Et- n-Hu- FO- F- Ph- , H- ?- (C'.-'.3) .-:.~:
74. 105 Et- n-Hu- HO- H- Ph- F:- ?-C 3S02N.'-'.'.-''75 106 Et- n-3u- F.0- H- Ph- H- ?-3r-C 2-CONz-76 10? n-3u- Et- Fi0- F:- p-n-CiaFZi- F- 7_NHZ--0-Ph-77 108 Et- n-Hu- F:0- F:- Ph- H- 7-. CSH1ICONr-78 109 Et- n-3u- f0- H- p-n-CipFZi- H- ?-N'~2_ -0-Ph-7g 110 Et- n-Hu- HO- H- Ph- H- ?-CH3CONF-80 111 n-8u- Et- HO- H- p-EO-Ph- F~- ?-NH2-81 113 Et- n-Hu- HO- H- p-HO-Ph- H- ?-NHZ-82 114 Et- n-Bu- fi0- F- p-CH30-Ph- H- ?-NHZ_ 83 115 n-3u- Et- HO- H- p-CH30-Ph- H- 7-N~-CBZ

84 116 Et- n-Hu- HO- H- p-Cfi30-Ph- H- ?-NH-CH2 ~.~.3 I I

85 11? n-Hu- Et- HO- H- Ph- H- 7-NH-CHZ

86 118 Et- n-Bu- HO- H- ph- H- ?-NH-CHZ

87 119 Et- n-Hu- HO- H- ph- H- ?-NHC02-t-' Bu 88 120 n-Bu- Et- HO- H- ph- H- ?-NHCOZ-t-Bu 89 121 Et- n-Bu- HO- H- Ph- H- ?-NHZ-90 122 n-Hu- Et- HO- H- Ph- H- ?-NH2-. ~' 91 123 Et- n-Bu- Fi0-H- Ph- H- ?-n-C6H13-NH-92 124 n-Bu- Et- HO- H- Ph- H- ?-n-C6~13-NF:-62 125 Et- n-3u- FO- H- Ph-~ H- I-, 8-.. (CH3) 3 N+( C ZCFZO) 3-93 126 n-3u- Et- EO- H- p-=-?h- H- ?-NFi-C32 94 12? n-Bu- Et- HO- H- p-: -?h- H- ?-N =2-95 128 Et- n-Hu- F:O-E- p-F-?h- E- ?-NF:-CBZ

96 129 Et- n-Bu- HO- H- p-F-?h- H- ?-NH2-97 130 Et- n-BL- HO- H- Ph- F:- I-, 8-(CH3) 3N~

98 132 Et- n-9u- HO- H- Ph- H- 8-phthal-imidyl-C sH 120-99 133 Et- n-Bu- HO- H- Ph- H- _.______8-n-C~pH21-52 134 Et- n-Hu- HO- H- Ph- H- 8- I-(C2H44)3-100 136 Et- n-Bu- HO- H- Ph- H- 8- HO-aa~

101 138 n-Bu- Et- HO- H- Ph- H- 8- CH3C02-49 90 Et- n-Bu- H- HO- H- m-CH30-Ph- 7-CH3S-49 91 Et- n-Hu- HO- H- m-CH30-Ph- H- 7-CH3S-48 89 Et- n-Hu- HO- , H- p-F-Ph- H- 7- (N) -azetidine 34 66 Et- n-Bu- HO- H- m-Cr30-?h- H- 7-C30-34 65 Et- n-Hu- H- EO- H- n-C 30-Ph- 7-C.'-'.30-35 68 Et- n-Hu- F:0-F:- n-CF 3-Ph- H- 7-C 30-35 67 Et- n-Hu- F:- F:O- H- -- m-C= 3-Ph- 7-C30-46 87 Et- n-3u- F:O-F:- r.,-'.-:0-?h-F:- 7-.'-0-46 86 Et- n-3u- F:O-F:- n-'.-0-?h- F:- 7-Ct 36 70 Et- n-3u- HO- F:- p-F -?h- F:- 7-C:~30-36 69 Et- n-8u- H- F:O- F- p-=-Bh- 7-Ct30-47 88 Et- n-Bu- FO- Fi- p-F -Ph- F:- 7-HO-39 76 Et- n-8u- EO- H- n-C:i30-Ph-H- 7-Br-39 75 Et- n-Hu- H- HO- F~'.- m-Cc:30-Ph- 7-Hr-40 77 Et- n-3u- H- HO- H- p-F-Ph- ?-F-40 78 Et- n-Bu- HO- H- p-F-Ph- H- 7-F-41 79 Et- n-Hu- H- HO- H- m-CH30-Ph- 7-F-41 80 Et-~ ~ n-Hu-HO- H- m-CH30-Ph- ~ H- 7-F-37 ?2 Et- n-Bu- HO- H- n-F-Ph- H- 7-CH30-38 73 Et- n-Bu- H- HO- H- o-F-Ph- 7-CH30-37 71 Et- n-Hu- H- F~:O-H- m-F-Ph- 7-CH30-a a.5 I i 38 74. Et- n-Hu- HO- H- o-F-Ph- H- ?-CH30-42 81 Et- n-Bu- HO- H- p-F-Ph- H- 7-CH3S-45 85 Et- n-Hu- HO- H- p-F-Ph- H- 7-CH3-45 84 Et- n-Hu- H- HO- H- p-r-Ph- 7-CH3-44 83 . Et- 'n-Hu- HO- H- p-F-Ph- H- 7- (N) -morpholine 43 82 Et- n-Hu- HO- H- p-F-Ph- H- 7-(N)-pyrroli -dine 64 286 Et-~ Et- HO- H- Ph- H- 7-Nr-C3Z

65 287 Et- Et- HO- F:- Ph- H- 7-N'.-'.Z_ ~

66 288 CH3- CH3- HO- F- Ph- H- 7-Nr2-67 289 n= n- EO- H- Ph-. H- 7_N2_ C3r7_ C3r7-68 290 n-Hu- n-3u- HO- H- Ph- H- 7-N=2-69 291 n-3u- n-3u- H0- L- Ph- H- 7-Nr-C3Z

70 292 n-Hu- n-3u- HO- H- p-F-Ph- H- 7-NHZ-71 293 n-8u- n-Hu- F:0-H- Ph- H- 7-PhCHZN-72 294 n-3u- n-3u- HO- H- Ph- H- 7- (C H3) 63 295 Et- n-Hu- HO- H- p-I- H- 7-NF:2-(C2Hq0)3-Ph-102 296 Et- n-Bu- HO- H- I-, p- H- 7-NH2-(CH3) 3N+(C2 Hq0) 3-Ph-~a~

Bridged Eenzothiepheaes (;101,112,131,135,137,139-14I) r O
HN~
O
CPD T101 (Dc. 59) C? D ~ I 12 ( E5c . 53 ) CPDs131 (Dc. 56) a a~

CPD X135 (Dt. 55) CPD 1137 (Fx. 57) CPD X139 (Dc. 58) aag O
oiyethyleneglycol 3400 MW polyethyleneglycol bridge CPD 1140 (~c. 51) ~O~O~
OCH3 ~' N C
O
HO
~" E~ C? D T 1 41 ( Dc . 50 ) Examples 104-231 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 4. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5-positions (R', R', Rs, R') and in the indicated position on the benzo ring (R").

Alternative compounds ~1 (a302-312, 314-430) S
s ~ ~ ..~,,. Ec n-Bu J
~.
Rs ox Cpd# RS
(Rx) 302 p-F-Ph- ?-(1-aziridine) 303 p-F-Ph- 7-EtS-304 p-F-Ph- 7-Ci:3S (0)-305 p-F-Ph- ~_CL3S(0)2-306 p-F-Ph- '.~.- 7-PhS-307 p-F-Ph- 7-Cz3S-g-Cg3S-3 0 8 p-F-P h- 7-C:i30-g-CL30-309 p-F-Ph- 7-Et-310 p-F-Ph- 7-iPr-311 p-F-Ph-7-t-Bu-312 p-F-Ph- 7-(1-pyrazole)-314 m-CH30-Ph 7-(1-azetidine) 315._...____ .. ..__._m_-~H3~-Ph-7-(1-aziridine).
._.

316 m-CH30-Ph-. 7-EtS-317 m-CH30-Ph- _ '7-CF:3S (0) -_ 318 m-CH30-Ph- 7-CH3S(0)2-319 m-CH30-Ph- 7-PhS-~3~

I I

320 m-CH34-Ph 7-CH3S-321 m-CH30-Ph 7-CH30-322 m-CH30-Ph 7-Et-323 m-CH30-Ph 7-iPr-324 m-CH30-Ph 7-t-Bu-325 p-F-Ph- 6-CH30-326 p-F-Ph- 7-(1-az~tidine) 327 p-r-ph- 7-EtS-_ c_CH3-328 p-F-Ph- 7-C 3S (O)-329 p-F-Ph- 7-CL3S(O)2-330 p-F-Ph- 7-PhS-g-CH3-331 p-F-Ph- 7-CH3S-332 p-F-Ph- 7-CH30-g-CH3-333 p-F-Ph- 7-CH3-_. 3 p-F-P h- _ _? -CH3o_ _ 9-CH3o-335 p-F-Ph- 7-(1-pyrrole) 336 p-F-Ph- 7- (N)-.~1' -methylpiperazine ~ 3 ~-337 p-F-Ph- Ph-338 p-F-Ph- 7-CH3C (=CH2) -339 p-F-Ph- 7-cyclpropyl 340 p-F-Ph- 7- (CH3) 2NH ' 341 p-F-Ph- 7-(N)-azetidine 342 p-F-Ph- 7-(N-pyrrolidine) 343 p-F-Ph- 7-(CH3)2N-344 m-CH30-Ph- 7-(1-pyrazole) 345 m-C 30-Ph- 7- (Ny~1' =methyl piperazine 34 6 m-CH30-Ph- Ph-347 m-CH30-Ph- ?-C3C (C~=2) -348 m-C'.-'.30-Ph- 7-cycl opropyl 349 m-CH30-Ph- 7- (C 3) ZNH -350 m-CH30-Ph- 7-(N)-azetidine 9-cH3s-351 m-CH30-Ph- 7-(N-pyrrolidine)-352 m-CH30-Ph- 7- (CH3) 2N-353 m-CH30-Ph- 6-CH30-354 m-CH30-Ph- ?-(1-azetidine) ~ 33 I I

355 m-CH30-Ph- 7-EtS-9-CH3_ 356 m-CH30-Ph- 7-CH3S (0) -9-cH3-357 m-CH30-Ph- ~ 7-CH3S (O) 2-358 m-CH30-Ph- 7-PhS-9-CH3_ 359 m-CH30-Ph- 7-cH3S-9-cH3-360 m-CH30-Ph- 7-CH30-361 m-CH30-Ph- 7-CH3-9-CH3_ 362 m-CH30-Ph- 7-CH34- _ 363 thien-2-yl 7-(1-aziridine) 364 thien-2-yl 7-EtS-365 thien-2-yl 7-CH3S(O)-366 thien-2-yl 7-CH3S(O)2-367 thien-2-yl 7-PhS-368 thien-2-yi 7-CH3S- -369 thien-2-yl 7-CH30-370 thien-Z-yl 7-Et- .

371 thien-2-yl 7-iPr-372 thien-2-yl ~ 7-t-Bu-373 thien-2-yl 7-(1-pyrrole)-374 thien-2-yl 7-CH3~-' a3ø

3?5 thien-2-yl ?-CH3S-3?6 thien-2-yl ?-(1-azetidine) 3?? thien-2-yl ?-Me-3?8 5-C1-thien-2-yl ?-(1-azetidine) 3?9 5-C1-thien-2-yl ?-(1-aziridine) 380 5-Cl-thien-2-yl ?-EtS-381 5-Cl-thien-2-yl ?-CH3S(O)-382 5-C1-thien-2-yl ?-CH3S(O)2-383 5-Cl-thien-2-yl 7-PhS-384 5-Cl-thien-2-yl ?-CH3S-385 5-Cl-thien-2-yl ?-CH3~-386 5-C1-thien-2-yl ?-Et-38? 5-Cl-thien-2-yl 7-iPr-388 5-Cl-thien-2-yl ?-t-3u-389 5-C1-thien-2-.;' 7-CH30-390 5-C1-thien-2-yl ?-CH3S-391 5-Cl-thien-2-yl ?-Me 392 thien-2-yl ?-(1-azetidine) 393 thien-2-yl ?-EtS--_ ~ g-CH3-3 g4 thien-2-yl ?-CIi3S (0) -395 thien-2-yl ?-CH3S (0) 2-g-CH3-a 35 396 thien-2-yl 7-PhS-397, thien-2-yl 7-CH3S-9-cH3_ 398 thien-2-yl ?-CH30-9-CHg-399 thien-2-yl 7-CH3-400 thien-2-yl 7-CH30-401 thien-2-yl 7-(1-pyrazrole) 402 thien-2-yl ?- (NrV'-sethylpiperazine 403 thien-2-yl Ph-404 thien-2-yl 7-CL3C(=CH2)-405 thien-2-yl 7-cyclpropyl 40fi thien-2-yl 7-(CH3)2NH -407 thien-2-yl 7-(N)-azetidine 408 thien-2-yl 7-(N-pyrrolidine) 409 thien-2-yl 7-(CH3)yN-9-CH3S- .

411 5-CI-thien-2-yl 7-(1-pyrazrole) 412 5-C1=thiea-2---yl- ----- 7= (N)~.~1' -methylpiperazine ---413 5-C1-thien-2-yl Ph-414 5-C1-thien-2-yl '7-CH3C(=CH2)-415 5-C1-thien-2-yl 7-cyclopropyl 416 5-C1-thien-2-yl 7- (CH3) 2NH -~3~

417 5-Cl-thien-2-yl 7-(N)-azetidine - 9-CH3s-418 5-Cl-thien-2-yl 7-(N-pyrrolidine)-9-cH3s-419 5-Cl-thien-2-yl 7-(CH3)2N-420 5-CI-thien-2-yl 7-(1-azetidine) g_CH3_ 421 5-C1-thien-2-yl ?-EtS-9-CH3_ 422 5-Cl-thien-2-yl 7-CH3S(O)-423 5-Cl-thien-2-yl "'7-CH3S(0)2-g-CH3-424 5-C1-thien-2-yl ?-PhS-9-CHg-425 5-C1-thien-2-yl 7-CH3S-426 5-C1-thien-2-yl 7-CH30-427 5-C1-thien-2-yl 7-CH3-428 5-C1-thien-2-yl 7-CH30-429 thien-2-yl 6-CH30-?-cH3o-_8-CH30=_ 430 5-Cl-thien-2-yl 6-CH30-23~

Fxamules 232-1394 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 1. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5-positions (R', R', Rs, R') and in the indicated position on the benzo ring (R").
Example 1395 Dibutyl 4-fluorobenzene dialdehyde O~~ ~%
/S ,,Bu ,"
Bu OHC
F
Br Preparation of dibutyl 4-fluoro benzene dialdehyde To a stirred solution of 17.5 g (123 mmol) of 2.5-difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at ambient temperature was added 6.2 g (135 mmol) of lithium sulfide (Aldrich). The dark red solution was stirred at 75 C for 1.5 hours, or until-the starting material was completely consumed, ar_d then 34 g 1135 mmol) of dibutyl mesylate aldehyde was added at. about 50 C. The reaction mixture was stirred at 75 C for three hours or until the reaction was completed. The cooled solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water several times, dried (MgSO,) and a 3B

concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 23.6 g (59%) of fluorobenzene dialdehyde as a yellow oil: 1H NMR
-. (CDC13) d 0.87 (t, J = 7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.78 (m, 4H), 3.09 (s, 2H), 7.2-7.35 (m, 1H), 7.S-7.6 (m, 2H) , 9.43 (s, 1H) , 10.50 (d, J = 2.62 Hz. 1H) .
Preparation of dibutyl 4-fluorobenzyl alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at -60 C was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C for hours. To the cooled solution at -40 C was added sufficient amount of ethyl acetae to quench the excess 15 of DIBAL, followed by 3 N HC1. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO,), and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 13.5 g (58%) of recovered starting material, and 8.1 g 20 (36%) of the desired fluorobenzyl alcohol as a colorless oil: 1H NMR (CDC13) d 0.88 (t, J = 7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J = 8.46, 3.02 Hz, 1H), 7.20 (dd, J = 9.47, 2.82 Hz, 1H). 7.42 (dd, J = 8.67, 5.64, 1H), 9.40 (s, 1H).
Preparation of dibutyl 4-fluorobenzyl bromide To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained from Step 2 in 100 mL of DMF at -40 C was added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich). The resulting solution was stirred cold for 30 min, then was allowed to warm to 0 C:--To-~
the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was.washed a few~times with water, dried (MgS04), and concentrated in'vacuo.
The mixture was stirred in small amount of ethyl acetate/hexane mixture (1:4 ratio) and filtered through a pad of silica gel, eluting with same solvent mixture.
a3°t The combined filtrate was concentrated in vacuo to give 9.5 g (98%) of the desired product as a colorless oil:
1H NMR (CDC13) d 0.88 (t, J =.7.05 Hz, 6H). 1.0-1.4 (m, 8H), 1.55-1.78 (m, 4H), 3.11 (s, 2H), 4.67 (s, 2H), S 7.02 (dt, J = 8.46, 3.02 Hz, 1H), 7.15 (dd, J = 9.47, 2.82 Hz, 1H), 7.46 (dd, J = 8.67, 5.64, 1H), 9.45 (s, 1H ) .
Step 4: Preparation of sulfonyl 4-fluorobenzyl bromide To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3 in 200 mL of CH,C1= at 0 OC was added 15.9 g (60 mmol) of mCPBA (64$ peracid). The resulting solution was stirred cold for 10 min, then was allowed to stirred ambient temperature for 5 hours. To the mixture was added 10~ solution of sodium sulfite and ethyl acetate. The extract was washed several times with saturated NasCO,, dried (MgSO,), and concentrated in vacuo to give 10.2 g (98~) of the desired product as a colorless oil: IH NMR (CDC13) d 0.91 (t, J = 7.05 Hz, 6H), 1.03-1.4 (m, 8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m, 2H), 3.54 (s, 2H), 5.01 (s, 2H), 7.04-7.23 (m, IH), 7.30 (dd, J = 8.87, 2.42 Hz, 1H), 8.03 (dd, J = 8.86, 5.64, 1H), 9.49 (s, 1H).
~~.0 Example 1396 o ~oH
a~ ~

WO 98/403?5 PGT/US98/03?92 Generic Scheme X
F 1. Li S, DMSO, heat S ,R' 2 x _..! \ R2 Rx ~ ~ R ~~ CHO
2. mesylate aldehyde, heat CHO
CHO
I. BuLi. PMETA
-40 °C, THF
2. DMF
I DIBAL, THF
Nw N
w F PMETA: iN''~ ~ ' -40 °C
Rx ~~
r S Rt BrPh3PBr, -40 °C R I ~ S 'R' Rz Rx , ~ R2 x ~ CHO
i OHC DMF
HO
Br mCPBA
O, S~O ,Rt RS B(OR~, heat O: S'~R 2 i Rx ~ O~ R2 ~ Rx / OHC R
Pd(Ph3P),t, Na2C03 gr EtOH, toluene or DME
R
or RS SnR3, heat Pd(Ph3P)4, solvent . base; e.g. KOtBu R = H, or short alkyl (C1-C6) O; S'O Rt _.. _. _~ :___.___ Rx , R2 / ~~~OH
R5.
Generic Scheme X: The nucleophilic substitution of an appropriately substituted 2-fluorobenzaldehyde with lithium sulfide or other nucleophilic sulfide anion in polar solvent (such as DMF, DMA, DMSO, etc), followed _ by the addition of dialkyl mesylate aldehyde (X), provided a dialkyl benzene dialdehyde Y. DIBAL
reduction of the dialdehyde at low temperature yielded benzyl alcohol monoaldehyde Z. Conversion of benzyl alcohol to benzyl bromide, followed by oxidation of sulfide to sulfone yielded the key intermediate W.
~~g~aration of N-DroDVlsulfonic acid To a solution of 51 mg (111 dun) Compound X in ethanol (400 ul) was added 1,3 propane sultone (19.5 ul, 222 dun). The reaction was stirred in a sealed vial at 55 for 25 hr. Sample was concentrated under a nitrogen stream and purified by reversed phase chromatography using acetonitrile/water as eluent (30-45%) and afforded the desired material as an off-white solid (28.4 mg, 44%): 'H NMR (CDCL,) d 0.82-0.96 (m, 6H), 1.11-1.52 (m of m, 10H), 1.58-1.72 (m, 1H), 2.08-2.21 (m, 1H), 2.36-2.50 (m, 2H), 2.93 (s, 6H), 3.02-3.22 (m of m, 5H), 3.58-3.76 (m, 2H), 4.15 (s, 1H), 5.51 (s, 1H), 6.45-6.58 (m, IH), 6.92-7.02 (m, 1H), 7.35-7.41 (m, 1H), 7.41-7.51 (m, 2H), 8.08 (d, J = 8.1 Hz, 1H), 8.12-8.25 (m, 1H); MS ES- M-H m/z 579.
3 0 F'.xamn a 13 9 7 The 7-fluoro, 9-fluoro and 7,9-difluoro analogs of benzothiepine'compounds of this invention can-be reacted with sulfur and nitrogen nucleophiles to give the corresponding sulfur and nitrogen substituted analogs. The following example demonstrates the synthesis of these analogs.
3,3-Dibutyl-5a-(4'-fluoropheayl)-4a-hydroxy-7-methylthio-2,3,4,5-tetrahydrobeazothiepiae-1,1-dioxide.
a~3 O' /O
\ S~ Bu Bu MeS
~OH
i F
A mixture of 0.4 g Of 3,3-dibutyl-7-fluoro-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, prepared by previously described method, 0.12 g of sodium methanethiolate and 20 ml of DMF was stirred at 50 C
for 3 days. An additional 0.1 g of sodium methanethiolate was added to the reaction mixture and the mixture was stirred for additional 20 h at 50 C
then was concentrated in vacuo. The residue was triturated with water and extracte wiith ether. The ether extract was dried over MgS04 and concentrated in vacuo to 0.44 g of an oil. Purification by HPLC (10%
EtOAc in hexane) gave 0.26 g of needles, mp 164-165.5 %C.
3,3-Dibutyl-9-dimethylamino-7-fluoro-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide and ?,9-Bis(dimethylamino)-3,3-dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide.
Me2N Oy /O Me2N .os O
Bu \ \iBu ~ Bu ~ Bu Me 2N
F ~OH
~OH
1 i i F
F
~4~

WO 98/40375 PCT/US9$/03792 A solution of 0.105 g of 3,3-dibutyl-7,9-difluoro-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, prepared by the method described previously, in 20 ml of 2 N
dimethylamine in THF was heated at 160 C in a sealed Parr reactor overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with 25 ml of water and extracted with ether. The ether extract was dried over MgS04 and concentrated in vacuo.
The resdue was purified by HPLC (10% EtOAc in hexane) to give 35 mg of an earlier fraction which was identified as 3,3-dibutyl-9-dimethylamino-7-fluoro-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 480 (M+ +1), and 29 mg of a later fraction which was identified as 7,9-bis(dimethylamino)-3,3-dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 505 (M+ +1) .
The compounds of this invention can also be synthesized using cyclic sulfate (A, below) as the reagent as shown in the following scheme. The following example describes a procedure for using the cyclic sulfate as the reagent.
ass I I

R SOC12 Rt 2 RuCl3, NaI04 Rt 1 ' ~ ' OH OH O\ /O O\ /O
O~ O
O
A
SH
I.NaH, diglyme t2 (Rx)q f(Rx)c PCC, / c 1~,,Gti Rt R2 (RY)P ~ ln. !
P
2.
O\ /O
OS O
3. H2S04 Rt O
O~S~ Rt RZ
(Rx)c O H (Rx)q H
O
p _ KOtBu (Rx)i (RY)P
Dibutyl cyclic sulfites ~. 46 R.
,S.
A solution of 2,2-dibutyl-1,3-propandiol (1038, 0.548 mol) and triethylamine (2218, 2.19 mol) in anhydrous methylene chloride (500 ml) and was stirred at 0 degrees C under nitrogen. To the mixture, thionyl chloride (97.8 g, 0.82 mol) was added dropwise and within 5 min the solution turned yellow and then turned black when the addition was completed within half an hour. The reaction mixture was stirred for 3 hrs. GC showed that there was no starting material left. The mixture was washed with ice water twice then with brine twice. The organic phase was dried over magnesium sulfate and concentrated under vacuum to give the cyclic sulfite 128 g (100~s) as a black oil. Mass spectrum (MS) was consistent with the product.
To a solution of the above compound (127.58 , 0.54 mol) in 600 ml acetonitrile and 500 ml of water cooled in an ice bath under nitrogen was added ruthenium(III) chloride (1 g) and sodium periodate (233 g, 1.08 mol).
The reaction was stirred overnight and the color of the solution turned black. GC showed that there was-no starting material left. The mixture was extracted with 300 ml of ether and the ether extract was washed three -.-times.withbrine.._The_organic_phase was dried over magnesium sulfate and passed through celite. The - 30 filtrate was concentrated under vacuum and gave the cyclic sulfate 133 g (97.80 as an~oil. Proton, carbon NMR and MS were consistent with the product.
2-((2-(4~-Fluorobenzyl)-4-methylpheaylthio)methyl -2-butylhexanol:

F
Sodium hydride (60% oil dispersion), 0.27 g (6.68 mmole), was washed with hexane and the hexane wash was decanted. To the washed sodium hydride was added 20 ml of 2-methoxyethyl ether (diglyme) and the mixture was cooled in an ice bath. A solution of 1.55 g (6.68 mmole) of 2-(4'-fluorobenzyl)-4-methylbenzenethiol in 10 ml of 2-methoxyethyl ether was added dropwise to the reaction mixture in 15 min. A mixture of 2.17 g (8.68 mmole) of the dibutyl cyclic sulfate in 10 ml of 2-methoxyethyl ether was added once and stirred for 30 min at 0 C then at room temperature for 1 hr under nitrogen. GC showed that there was no thiol left. The solvent was evaporated and triturated wth water then was extracted with ether twice. The water layer was separated, treated with 20 ml of 10% NaOH then was boiled for 30 min and cooled, acidified with 6N HC1 and boiled for 10 min. The reaction mixture was cooled and extracted with ether. The organic layer was washed successively with water and brine, dried over magnesium 25- -sulfate and ~ concentrated under vacuum -to--give--2._.47 g ( 92.5%) of an oil. Proton NNgt , 13C NMR and MS were consistent with the product.
2-[(2-(4'-Fluorobenzyl)-4-methylphenylthio)methyl]-2-butylhexanal:

I-i3C A~
off I
F
To a solution of the above product (2 g , 9.9 mmol) in 40 ml methylene chloride cooled in an ice bath under nitrogen was added pyridinium chlorochromate (2.18 g, 9.9 mmol) at once. The reaction was stirred with 3 hrs and filtered through a bed of silica gel.
The filtrate was concentrated under vacuum to give 1.39 g (70%) of an oil. Proton, carbon Nt~t and MS were consistent with the product.
2-[(Z-(4~-Fluorobenzyl)-4-methylphenylsulfonyl)methyl]-2-butylhexanal ~°s H3C f~ p H
L
I
,r F..
To a solution of the above product (0.44 g ,l.l - mmole) in 20 ml methylene chloride solution cooled in an ice bath under nitrogen was added 70% m-chloroperbenzoic acid (0.54 g, 2.2 mmol) at once. The reaction mixture was stirred for 18 hrs and filtered.

The filtrate was washed successively with 10% NaOH
(3X), water and brine, dried over magnesium sulfate and concentrated under vacum to give 0.42 g (90%) of an oil. Proton, carbon NMR and MS were consistent with the product.
3,3-Dibutyl-7-methyl-Sa-(4~-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide:
H 3 C ~ off i F
A mixture of 0.37 g (0.85 mmol) of the above product in 30 ml of anhydrous THF was stirred at 0 %C.
Then potassium t-butoxide (102 mg, 0.85 mmol) was added. After 3 hrs, TLC showed that there was a product and some starting material left. The crude reaction mixture was acidified with 10% HC1 and extracted with ether. The ether extract was washed successively with water and brine, dried with MgS04 and concentrated under vacuum. The residue was purified by HPLC (10%
EtOAc-Hexane). The first fraction was 0.1 g of starting material as an oil and the second fraction was a white ' solid. 0.27 g (75%). Proton NMR and carbon NMR were consistent with._the desired product. Mass.spectrum (CI) _ also confirmed the product, m/e 433 (M+ 1).
as o Step 1 CmHioClNO, fw=291.69 In an inert atmosphere, weigh out 68.3 gms phosphorus pentachloride (0.328mo1e Aldrich 15,777-5) into a 2-necked 500m1 round bottom flask. Fit flask with a N= inlet adapter and subs seal. Remove from inert atmosphere and begin N= purge. Add 50m1s anhydrous chlorobenzene (Aldrich 28,451-3) to the PC1, via syringe and begin stirring with magnetic stir bar.
Weigh out 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole Aldrich 12,511-3). Slowly add to the chlorobenzene solution while under N= purge. Stir at room temperature overnight. After stirring at room temperature for -20hrs,.place in oil bath and heat at 50C for lhr. Remove chlorobenzene by high vacuum. Wash residue with anhydrous hexane. Dry acid chloride wt=61.95gms. Store in inert and dry atmosphere.
In inert atmosphere, dissolve acid chloride with 105m1s anhydrous anisole (0.97 mole Aldrich 29,629-5).
__--_P.1_ace__ solution in-__a .2-necked..-50-Oml_ round- bottom flask-.
Weigh out 45.lgms aluminum chloride (0.34 moles Aldrich 29,471-3) and place in a solid addition funnel.
Fit reaction flask with addition funnel and a N= inlet adapter. Remove from inert atmosphere. Chill reaction solution with ice bath and begin N= purge. Slowly add AlCl, to chilled solution. After addition is complete, allow to warm to room temperature. Stir overnight .
oc5 ~

Quench reaction by pouring into a solution of 300 mls 1N HC1 and ice. Stir 15 min. Extract twice with ether. Combine organic layers and extract twice with 2% NaOH, then twice with deionized H=O. Dry with MgSO,, filter and rotovap to dryness. Remove anisole by high vacuum. Crystalize product from 90% ethanol 10% ethyl acetate. Dry on vacuum line. Wt=35.2gms. Yield 41%.
Obtain NMR and mass spec (m/z=292).
Step 2 Dissolve 38.lOgms (0.131 moles) of the benzophenone from step 1 in 250m1s anhydrous methylene chloride. Place in a 3 liter flask fitted with N=
inlet, addition funnel and stopper. Stir with magnetic stir bar. Chill solution with ice bath.
Prepare a solution of 39.32 gms trifluoromethane sulfonic acid (0.262 mole Aldrich 15,853-4) and 170 mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N,.
Stir 5 minutes after addition is complete.
Prepare a solution of 22.85 gms triethyl silane (0.197mo1e Aldrich 23,019-7) and 170m1s anhydrous iriethyleae chloride-- Place in-addition funnel-and add dropwise to chilled solution under N=. Stir 5 minutes after addition is complete.
Prepare a second solution of 39.32 gms trifluoromethane sulfonic acid and~170m1s anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N=. Stir 5 minutes after addition is complete., as~-Cl,HISC1N0, fw=277.71 wo 9s~ao3~s rcr~s9sio3~n Prepare a second solution of 22.85 gms triethyl silane and 170m1s anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N,. After all additions are made allow to slowly warm to room temperature overnight. Stir under N, overnight.
Prepare 1300 mls saturated NaHCO, in a 4 liter beaker. Chill with ice bath. While stirring vigorously, slowly add reaction mixture. Stir at chilled temperature for 30 min. Pour into a separatory funnel and allow separation. Remove organic layer and extract aqueous layer 2 times with methylene chloride.
Dry organic layers with MgSO,. Crystallize from ethanol. Dry on vacuum line. Dry wt=28.8gms. Confirm by NMR and mass spec (m/z=278).
Step 3 C=sH"NO,S fw=443.61 Dissolve 10.12 gms (0.036 moles) of product 2 with 200 mls anhydrous DMSO. Place in a 500 ml round bottom flask with magnetic stir bar. Fit flask with water condenser, N, inlet, and stopper. Add 1.84 gms Li=S
(0.040 moles Aldrich 21,324-1). Place flask in oil bath and heat at 75°C under N, overnight then cool to room temperature.
Weigh out 10.59 gms dibutyl mesylate (0.040 moles). Dissolve with anhydrous DMSO and add to reaction solution. Purge well with N,, heat overnight a53 at 80'C.
Cool to room temperature. Prepare 500 mls of 5%
acetic acid in a 2 liter beaker. While stirring.
slowly add reaction mixture. Stir 30 min. Extract with ether 3 times. Combine organic layers and extract with water and sat'd NaCl. Dry organic layer with MgSO,, filter and rotovap to dryness. Dry oil on vacuum line. Obtain pure product by column chromatography using 95% hexane and 5% ethyl acetate as the mobile phase. Dry wt=7.8 gms. Obtain NMR and mass spec (m/z=444).
Step 4 C,SH~~N06S fw=47 5 . 61 Dissolve 9.33 gms (0.021 moles) of product 3 with 12D mls anhydrous methylene chloride. Place in a 250 ml round bottom flask with magnetic stir~bar. Fit flask with N, inlet and stopper. Chill solution with ice bath under N= purge.. Slowly add 11.54_gms 3-chloroperbenzoic acid (0.0435 moles, Fluka 25800, -65%). After addition is complete warm to room temperature and monitor reaction by TLC. Reaction goes quickly to the sulphoxide intermediate but takes 8 hrs to convert to the sulphone. Chill solution over night in freezer. Filter solid from reaction, extract filtrate with 10% K~CO,. Extract aqueous layer twice with methylene choride. Combine organic layers and dry asp with MgSO,. Filter and rotovap to dryness. Obtain pure product by crystallizing from ethanol or isolating -. by column chromatography. Obtain NMR and mass spec (m/z=476).
Step 5 Reaction is done in a 300 ml stainless steel Parr stirred mini reactor. Place 9.68 gms (0.02'04 moles) of product 4 in reactor base. Add 160 mls ethanol. For safety reasons next two compounds are added in a N~
atmosphere glove bag. In glove bag, add 15.3 mls formaldehyde (0.204 moles, Aldrich 25,254-9, about 37 wt% in water) and 1.45 gms 10% Pd/Carbon (Aldrich 20,569-9). Seal reactor before removing from glove bag_ Purge reactor three times with H=. Heat to 55°C
under H=. Run reaction at 200 psig H,, 55°C, and a stir rate of 250 rpm. Run overnight under these conditions.
Cool reactor and vent H=. Purge with N=. Check progress of run by TLC. Reaction is a mixture of . desired product and intermediate. Filter reaction mixture over a bed of celite washing well with ether.
Rotovap and redissolve with ether., Extract with water.
Dry organic layer with MgSO,, filter and rotovap to dryness. Dry on vacuum line.
Charge reactor again with same amounts, seal reactor and run overnight under same conditions.
C"H"NO,S fw=473.68 After second run all of the material has been converted to the desired product. Cool and vent H, pressure.
Purge with N,. Filter over a bed of celite, washing well with ether. Rotovap to dryness. Dissolve with ether and extract with water. Dry organic layer with MgSO,, filter and rotovap to dryness. Dry on vacuum line. Obtain Nt~t and mass spec (m/z=474).
Step 6 'N
Z O HaC' \CH~
Cs,H"NO,S fw=473.68 Dissolve 8.97 gms (0.0189 mole) of product 5 with 135 mls anhydrous THF. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N= inlet and stopper. Chill solution with ice/sait bath under N= purge. Slowly add 2.55 gms potassium t-butoxide (0.227 mole Aldrich 15,667-1). After addition is complete, continue to stir at -10°C monitoring by TLC.
Once reaction is complete, quench by adding 135 mls 10$ HC1 stirring 10 min. Extract three times with ether. Dry organic layer with MgSO,, filter and rotovap to dryness. Crystallize from ether. Obtain NMR and mass spec (m/z=474).
Step 7 a56 WO 98!40375 PC"T/US98/03792 C"H"NO,S fw=459.65 Dissolve 4.67 gms (0.01 moles) of product 6 with 100 m1s anhydrous chloroform. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N=
inlet adapter and suba seal. Chill solution with dry ice /acetone bath under a N= purge. Slowly add, via syringe, 2.84 mls boron tribromide (0.03 moles Aldrich 20,220-7). Stir at cold temperature for 15 min after addition then allow to warm to room temperature.
Monitor reaction progress by TLC. Reaction is usually complete in 3 hrs.
Chill solution with ice bath. Quench with 100 mls 10% K,CO, while stirring rapidly. Stir 10 min. then transfer to sep funnel and allow separation. Remove aqueous layer. Extract organic layer once with 10%
HC1, once H=O, and once with saturated NaCl solution.
Dry organic layer with MgSO,, filter and rotovap to dryness. Crystallize product from ether. Obtain NMR
and mass spec (m/z=460).
Step 8 asp Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0 60% disp. in mineral oil) in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N, inlet and stopper. Chill NaH with ice bath and begin N, purge.
Dissolve 4.0 gms (8.7 mmoles) of product 7 with 60 mls anhydrous DMF. Add to the cold NaH. Stir at cold temperature for 30 min. Add 1.33 gms K=C0, (9.57 mmoles Fisher P-208).
Dissolve 16.1 gms 1,2-bis-(2-iodoethoxy)ethane (43.5 mmoles Aldrich 33,343-3) with 60 mls anhydrous DMF. Add to cold reaction mixture. Warm to room temperature then heat to 40°C overnight under N~.
Cleanup by diluting with ether and extracting sequentially with 5% NaOH, HBO, and saturated NaCl.
Dry organic layer with MgSO,, filter and dry. Obtain pure product by column chromatography using 75% hexane 25% ethyl acetate as the mobile phase. Obtain NNtR and mass spec (m/z=702).
Step 9 ~~8 C1=H"NO,SI fw=701.71 Dissolve 1.0 gms (1.43 mmoles) of product 8 with 10 mls anhydrous acetonitrile. Place in a 3 ounce Fischer-Porter pressure reaction vessel with magnetic stir bar. Add 2.9 gms tri~ethyl amine (28.6 mmoles Aldrich 23,962-3) dissolved in 10 mls anhydrous acetonitrile. Purge well with N, then close system .
Heat at 45°C. Monitor reaction by TLC. Reaction is usually complete in 48 hrs.
Perform cleanup by removing acetonitrile under vacuum. Redissolve with anhydrous chloroform and precipitate quaternary ammonium salt with ether.
Repeat several times. Dry to obtain crystalline product. Obtain NMR and mass spec (m/z=675).

C"H~,N~O,SI fw=802.90 ~~amnle 1399 Step 1. Preparation of 1 r -To a solution of 144 g of KOH (2560 mmol) in 1.1 L of DMSO was added 120 g of 2-bromobenzyl alcohol (641 mmol) slowly via addition funnel. Then was added 182 g of methyliodide (80 mL. 1282 mmol) via addition funnel.
Stirred at ambient temperature for fifteen minutes.
Poured reaction contents into 1.0 L of water and extracted three times with ethyl acetate. The organic layer was dried over MgSO, and concentrated n vacuo.
Purified by silica-gel chromatography through a 200 mL
plug using hexanes (100$) as elutant yielded 103.2 g (80$) of 1 as a clear colorless liquid. 1H NMFt (CDC1,) d 3.39 (s~ 3H). 4.42 (s. 2H), 7.18-7.27 (m, 2H), 7.12 (d~
- 7.45, 1H). 7.50 (s, 1H).
Step 2. Preparation of 2 To a cooled (-78 °C) solution of 95 g (472 mmol) of 1 in 1.5 L THF was added 240 mL of 2.5 M n-butyl lithium (576 mmol). The mixture was stirred for one hour, and then to it was added 180 g of zinc_iodide (566 mmol) dissolved in 500 ml THF.~ The mixture was stirred thirty minutes, allowed to warm to 5 C, cooled to -10 °C and to it was added 6 g of Pd(PPh,), (5.2 mmol) and 125 g 2,5-difluorobenzoyl chloride (708 mmol). The mixture was stirred at ambient temperature for 18 hoursand then cooled to 10 °C, quenched with water, partitioned between ethyl acetate and water, and washed a.6 o organic layer with 1N HCL and with 1N NaOH. The organic layer was dried over MgSO, and concentrated ~
vacuo. Purification by silica gel chromatography (Waters Prep-500) using 5% ethyl acetate/hexanes as elutant gave 53.6 g (43 %) of 2 as an orange oil. 1H
NMR (CDC1,) d 3.40 (s, 3H), 4.51 (s, 2H), 7.12-7.26 (m, 3H), 7.47 (t, J = 7.50, 1H), 7.57 (d, J = 7.45, 1H), 7.73 (d, J = 7.45, 1H), 7.80 (s, 1H).
Step 3. Preparation of 3 Bu ~Bu ,~O 'OH

A solution of 53 g (202.3 mmol) of 2 and 11.2 g Li2S
(242.8 mmol) in 250 mL DMF was heated to 100 °C for 18 hours. The reaction was cooled (0 °C) and 60.7 g of X
(the cyclic sulfate compound of example 1397) (242.8 mmol) in 50 mL DMF was added. Stirred at ambient temperature for 18 hours then condensed in vacuo.
Added 1 L water to organic residue and extracted twice with diethyl ether. Aqueous layer acidified (pH 1) and refluxed 2 days. Cooled to ambient temperature and extracted with methylene chloride, dried organic layer over MgSO, and condensed ~n vacuo. Purification by silica gel chromatography (Waters Prep-500) using 10%
ethyl acetate / hexanes as elutant gave 42.9 g (48-%) of 3 as a yellow oil. 1H NMR (CDC1,) d 0.86 (t, J = 7.25 Hz, 6H), 1.10 - 1.26 (m, 12H), 2.83 (s, 2H), 3.32 (s, 2H), 3.40 (s, 3H), 4.48 (s, 3H), 7.02 (dd, J = 8.26 Hz and 2.82 Hz, 1H), 7.16 (dt, J = 8.19 Hz and 2.82 Hz, 1H), 7.45 (t, J = 7.65 Hz, 1H), 7.56-7.61 (m, 2H), 7.69 (d, J = 7.85 Hz, 1H), 7.74 (s, 1H), Step 4. Preparation of 4 etlr t S~ gu ~Bu CH zOH

To a cooled (-40 °C) solution of 42.9 g (96.2 mmol) of 3 in 200 mL of methylene chloride was added 21.6 g trifluoromethane sulfonic acid (12.8 mL, 144 mmol) followed by the addition of 22.4 g triethyl silane (30.7 mL, 192.4 mmol). Stirred at -20 °C for two hours, quenched with water and warmed to ambient temperature.
Partitioned between methylene chloride and water, dried the organic layer over MgSO, and condensed ~i vacu Purification by silica gel chromatography (Waters Prep-500) using 10$ ethyl acetate/ hexanes as elutant gave 24.2 g (60~)of 4 as a oil. 'H NNgt (CDC1~) d 0.89 (t, J = 7.05 Hz. 6H), 1.17 - 1.40 (m, 12H), 1.46 (t, J = 5.84 Hz, 1H), 2.81 (s, 2H), 3.38 (s, 3H), 3.43 (d, J = 5.23 Hz, 2H), 4.16 (s, 2H), 4.42 (s, 2H), 6.80 (d, J = 9.67 Hz, 1H), 6.90 (t, J = 8.46 Hz, 1H), 7.09 (d, J = 7.45 Hz, 1H), 7.15 - 7.21 (m, 2H), 7.25 - 7.32 (m, 2H), 7.42 (m, 1H).
Step 5. Preparation of 5 Bu S~Bu CHO

To a cooled (15-18 °C) solution of 24.2 g (55.8 mmol) of 4 in 100 mL DMSO was added 31.2 g sulfur trioxide pyridine complex (195 mmol). Stirred at ambient temperature for thirty minutes. Poured into cold water and extracted three times with ethyl acetate. Washed organics with 5~ HC1 (300 mL) and then with brine (300 mL), dired organics over MgSO, and condensed ~n vacuo to give 23.1 g (96 ~) of 5 as a light brown oil. 'H NMR
a.6 ~.

(CDCl,) d 0.87(t, J 7.05 Hz, 6H), = 1.01 - 1.32 (m.

8H). 1.53 - 65 (m, 3.38 (s, 3H), 1. 4H), 2.98 (s, 2H), 4.15 (s, 2H).4.43 (s, 2H), 6.81 (dd. = 9.66 Hz and J

2.82 Hz, 1H).6.91 (t, J = 8.62 Hz. 1H),7.07 (d, J =

46 Hz 1H) 7.14 (s. 1H). 7.19 (d, 7.65 Hz, 1H), 7 J =

, , .42 (dd, J = 8.66Hz and 5.64 . - 32 Hz, 7.26 7. (m, 1H), 1H). 9.40 1H).
(s, Step 6. Preparation of 6 Bu ~Bu _ CHO

To a cooled (0 °C) solution of 23.1 g (53.6 mmol) of 5 in 200 mL methylene chloride was added 28.6 g meta cholorperoxy-benzoic acid (112.6 mmol). Stirred at ambient temperature for 24 hours. Quenched with 100 mL
10% Na,SO,, partitioned between water and methylene chloride. Dried organic layer over MgSO, and condensed ;n~acuo to give 24.5 g (98%) of 6 as a light yellow oil. 1H NMR (CDCl,) d 0.86 - 1.29 (m, 14H), 1.58 - 1.63 (m. 2H), 1.82 - 1.91 (m, 2H), 3.13 (s, 2H), 3.39 (s.
3H), 4.44 (s, 2H). 4.50 (s, 2H), 6.93 (d, J = 9.07 Hz.
1H). 7.1D - 7.33 (m, 5H). 8.05 (s. 1H). 9.38 (s, IH).
Step 7. Preparartion of 7 Bu ~J ~Bu CHO
Me J~ ~oLh 3 To a solution of 24.5 g (52.9 mmol) of 6 in 20 mL of THF contained in a stainless steel reaction vessel was added 100 mL of a 2.0 M solution of dimethyl amine and 20 mL of neat dimethyl amine. The vessel was sealed and heated to 110 °C for 16 hours. The reaction vessel was cooled to ambient temperature and the contents concentrated ~n-. Purification by silica gel chromatography (Waters Prep-500) using 15 % ethyl acetate/hexanes gave 21.8 g (84 %) of 7 as a clear colorless oil. 1H Nf~t (CDC1,) d 0.85 (t, J = 7.25 Hz, 6H), 0.93 - 1.29 (m, 8H), 1.49 - 1.59 (m, 2H), 1.70 -1.80 (m, 2H), 2.98 (s, 8H), 3.37 (s, 3H), 4.41 (s, 2H), 4.44 (s, 2H), 6.42 (s, 1H), 6.58 (dd, J - 9.0 biz and 2.61 Hz, 1H), 7.13 (d, J = 7.45 Hz, 1H), 7.21 (s, 1H), 7.28 (t, J = 7.85 Hz. 1H), 7.82 (d, J = 9.06 Hz, 1H), 9.36 (s, 1H) .
Step 8. Preparation of 8 O..S
Bu Me 2N
OH

A solution of 21.8 g (44.8 mmol) of 7 in 600 mL of THF
was cooled to 0 °C. 58.2 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5 °C. Stirred for 30 minutes, then quenched with 50 mL of saturated ammonium chloride.
The organic layer was partitioned between ethyl acetate and water, dried over MgS04 and concentrated ~n vacuo.
Purification by recrystalization from -10% ethyl acetate/hexanes gave 15.1 g of 8 as a white solid. The mother liquor was purified by silica gel chromatography (Waters Prep-500) using 30% ethyl acetate/hexanes as the elutant to give 3.0 g of 8 as a white solid. MS
(FABLE) m/e 494.6. HRMS (EI') calculated for M+H
487.2756. Found 487.2746.

Step 9. Preparation of 9 ,S~
~~Bu 8u Met ' ~yOH
\ Br A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of methylene chloride was cooled to -60 °C. 4.1 mL of a 1M solution of boron tribromide was added. Stirred at ambient temperature for thirty minutes. Cooled reaction to -10 °C and quenched with 50 mL of water.
The organic layer was partitioned between methylene chloride and water, dried over MgSO, and concentrated ~n vacuo. Purification by recrystalization from 50%
ethyl acetate/methylene chloride gave 1.95 g (89%) of 9 as a white solid. MS (FABH') m/e 537. HRMS (FAB) calculated for M 536.1834. Found 536.1822.
Step 10. Preparation of 10 O' SO
~iBu ~ Bu Me2N
~OH
\ I Br' A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62~
mmol) of pyridine in 30 mL of acetonitrile was stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo. Purification by -.--.--.
recrystallization from methanol/ diethyl ether gave 1.19 g (96%) of 10 as an~off white solid. MS (FAB') m/e 535.5.
a~~

Step 1. Preparation of 2 Bu ~8u CHO

To a solution of 6.0 g of dibutyl 4-fluorobenzene dialdehyde of Example 1395 (14.3 mmol) in 72 mL of toluene and 54 mL of ethanol was added 4.7 g 3-nitrobenzeneboronic acid (28.6 mmol). 0.8 g of tetrakis (triphenylphosphine) palladium(0) (0.7 mmol) and 45 mL
of a 2 M solution of sodium carbonate in water. This heterogeneous mixture was refluxed for three hours.
then cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO, and concentrated ~n~.
Purification by silica gel chromatography (Waters Prep-2000) using ethyl acetate/hexanes (25/75) gave 4.8 g (73%) of the title compound as a yellow solid. 1H NMFt (CDC1,) d 0.88 (t. J = 7.45 Hz. 6H), 0.99-1.38 (m. 8H).
1.62-1.75 (m, 2H), 1.85-2.00 (m, 2H). 3.20 (s. 2H).
4.59 (s. 2H). 6.93 (dd, J = 10.5 and 2.4 Hz, 1H). 7.15 (dt. J = 8.4 and 2.85 Hz, 1H). 7.46-7.59 (m. 2H). 8.05-8.16 (m, 3H). 9.40 ~s, 1H~.
arm Step 3. Preparation of 3 - Oo \ S~~Bu / ~ Bu y OH
NO Z
A solution of 4.8 g (10.4 mmol) of 2 in 500 mL THF was cooled to 0 °C in an ice bath. 20 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5 °C. Stirring was continued for 30 minutes, then the reaction was quenched with 100 mL
of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and water; the organic layer was washed with brine, then dried (MgSO,) and concentrated ~.n vacuo. Purification by silica gel chromatography through a 100 ml plug using CH~C1= as eluent yielded 4.3 g (90%) of 3 as a pale yellow foam.
1H NMFt (CDC1,) d 0.93 (t, J = 7.25 Hz. 6H) , 1.00-1.55 (m. 8H), 1.59-1.74 (m, 3H). 2.15-2.95 (m. 1H). 3.16 (q~, J~ = 15. 0 Hz, GV = 33 .2 Hz, 2H) . 4.17 (d. J =
6.0 Hz. 1H). 5.67 (s, 1H), 6.34 (dd, J=9.6 and 3.0 Hz, 1H). 7.08 (dt, J = 8.5 and 2.9 Hz,~ 1H). 7.64 (t, J =
8.1 Hz, 1H), 7.81 (d, J = 8.7 Hz. 1H), 8.13 (dd, J =
9.9 and 3.6 Hz. 1H), 8.23-8.30 (m. 1H). 8.44 (s. 1H).
MS(FABH+) m/e (relative intensity) 464.5 (100). 446.6 (65). HRMS calculated for M+H 464.1907. Found 464 .1905 = -___-Step 4. Preparation of 4 O.. ~O
~ ~S~iBu ~ eu Me2N ' ~~OH
NOZ
To a cooled (0 °C) solution of 4.3 g (9.3 mmol) of 3 in 30 ml THF contained in a stainless steel reaction vessel was added 8.2 g dimethyl amine (182 mmol). The vessel was sealed and heated to 110 °C for 16 hours.
The reaction vessel was cooled to ambient temperature and the contents concentrated ~n vacuo. Purification by silica gel chromatography (Waters Prep-2000) using an ethyl acetate/hexanes gradient (10-40% ethyl acetate) gave 4.0 g (88%) of 4 as a yellow solid. 'H
NMR (CDC1,) d 0.80-0.95 (m, 6H), 0.96-1.53 (m. 8H).
1.60-1.69 (m, 3H). 2.11-2.28 (m, 1H). 2.79 (s. 6H).
3.09 (qpg~ Jpg = 15.0 Hz, DV= 45.6 Hz, 2H). 4.90 (d, J
9.0 Hz. 1H). 5.65 (s. IH). 5.75 (d. J = 2.1 Hz, 1H), 6.52 (dd, J = 9.6 and 2.7 Hz. 1H). 7.59 (t. J = 8.4 Hz, 1H). 7.85 (d, J = 7.80 Hz, 1H), 7.89 (d. J = 9.0 Hz, 1H), 8.20 (dd, J = 8.4 and 1.2 Hz. 1H), 8.43 (s, 1H).
MS(FABH+) m/e (relative intensity) 489.6 (100). 471.5 (25). HRMS calculated for M+H 489.2423.. Found 489.2456.
a6g WO 98140375 PCf/US98/03792 Step 5. Preparation of 5 o,, p ~ ~SI~Bu Du Me2N
OH

To a suspension of 1.0 g (2.1 mmol) of 4 in 100 ml ethanol in a stainless steel Parr reactor was added 1 g 10% palladium on carbon. The reaction vessel was sealed, purged twice with H,, then charged with H= (100 psi) and heated to 45 °C for six hours. The reaction vessel was cooled to ambient temperature and the contents filtered to remove the catalyst. The filtrate was concentrated in vacuo to give 0.9 g (96%) of 5. iH
NMR (CDC1,) d 0.80-0.98 (m, 6H), 1.00-1.52 (m, lOH), 1.52-1.69 (m, 1H), 2.15-2.29 (m, 1H), 2.83 (s, 6H), 3 .07 (qAg, ,3p~g = 15.1 Hz, Dv = 44.2 Hz, 2H) , 3 .70 (s, 2H), 4.14 (s, 1H), 5.43 (s, 1H), 6.09 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 12.2 and 2.6 Hz, 1H), 6.65 (dd, J =
7.8 and 1.8 Hz, 1H), 6.83 (s, 1H), 6.93 (d, J = 7.50 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H). MS(FABH+) m/e (relative intensity) 459.? (100).
HRMS calculated for M+H 459.2681. Found 459.2670.
02~0~

Step 6. Preparation of 6 To a solution of 914 mg (2.0 mmol) of 5 in 50 ml THF
was added 800 mg (4.0 mmol) 5-bromovaleroyl chloride.
Next was added 4 g (39.6 mmol) TEA. The reaction was stirred 10 minutes, then partitioned between ethyl acetate and brine. The organic layer was dried (MgSO,) and concentrated ;n.~- Purification by silica gel chromatography through a 70 ml MPLC column using a gradient of ethyl acetate(20-50%) in hexane as eluent yielded 0.9 g (73%) of 6 as a pale yellow oil.
1H ~ (CDC1,) d 0.84-0.95 (m, 6H)' I.02-1.53 (m, lOH), 1.53-1.68 (m, 1H), 1.80-2.00 (m, 4H), 2.12-2.26 (m, 4H). 2.38 (t, J = 6.9 Hz, 2H), 2.80 (s' 6H), 3.07 (qpg, Jp~ = 15.6 Hz' DV = 40.4 Hz, 2H)' 3.43 (t, J = 6.9 Hz, 2H), 4.10 (s, 1H). 5.51 (s, 1H)' 5.95 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 9.3 and 2.7 Hz. 1H), 7.28 (s, 1H)' 7.32-7.41 (m. 2H). 7.78 (d, J = 8.1 Hz. 1H), 7.90 (d, J
9.0 Hz, 1H).
Step 7. Preparation of 7 O
O~S~
Bu ~ Bu Me 2N ~'OH
NEt3TFA
To a solution of 0.9 g (1.45 mmol) of 6 in 25 ml acetonitrile add 18 g (178 mmol) TEA. Heat at 55 °C
for 16 hours. The reaction mixture was cooled~to ambient temperature and concentrated ~n vacuo:', Purification by reverse-phase silica gel chromatography (Waters Delta Prep 3000) using an acetonitrile /water gradient containing 0.05% TFA (20-65% acetonitrile) ~'~ G

WO 98140375 PG"f/US98/03792 gave 0.8 g (73%) of 7 as a white foam. iH NMR (CDC1,) d 0.80-0.96 (m, 6H), 0.99-1.54 (m. 19H). 1.59-1.84 (m, 3H). 2.09-2.24 (m, 1H), 2.45-2.58 (m. 2H). 2.81 (s.
6H). 3.09 (qpg. JAg = 15.6 Hz, DV = 18.5 Hz, 2H). 3.13-3.31 (m, SH), 4.16 (s, 1H). 5.44 (s, 1H). 6.08 (d, J =
1.8 Hz, 1H), 6.57 (dd. J = 9.3 and 2.7 Hz, 1H). 7.24 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 8.4 Hz. 1H). 7.56 (d, J = 8.4 Hz, 1H), 7.74 (s. 1H). 7.88 (d. J = 9.O Hz, 1H), 9.22 (s, 1H). HRMS calcd 642.4304; observed 642.4343.
~?ramnl P 1 400 Step 1 off \ \
/ ~%
' C14H1302F fw=232.25 A 12-liter, 4-neck round-bottom flask was equipped with reflux condenser. N2 gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N2.
A slurry of sodium hydride (126.Og/4.988mo1) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4-fluorophenol (560.5g/5.000mo1) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C) for lh. A solution of 3-methoxybenzyl chloride (783.Og/5.OOOmo1) in toluene (?50 mL) was added via addition funnel while maintaining reflux.
After 15 h: refluxing, the mixture was cooled to room temperature and poured into H20 (2.5 L). After 20 min.
stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720g) in MeOH (2.5 L). The MeOH layer was added to 20% aqueous potassium hydroxide, and the ~'1 I

WO 98/40375 PC"T/US98/03792 mixture was stirred for 30 min. The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aq. KOH solutions were combined and acidified with concentrated HC1. The acidic solution was extracted three times with ethyl ether, dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil (449.Og/39%
yield). b.p.: 120-130 C/50mtorrHg. 1H NMR and MS [(M
+ H)+ = 233] confirmed desired structure.
Step 2 OI~M
C17H18N02FS fw=319.39 A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N2 gas adaptor. The system was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5g/1.961mo1) and dimethylformamide were added.
2D The solution was cooled to 6 C, and sodium hydride (55.5g/2.197mo1) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4g/1.961mo1) was added. After 15 h, the reaction mixture was poured into H20 (4.0 L), and extracted two times with ethyl ether. The combined organic layers were washed with H20 and saturated aqueous NaCl, dried (MgS04), filtered, and concentrated in vacuo to give the product (605.3g, 97% yield). 1H NMR and MS [(M+H)+
- 320] confirm desired structure.
a~ ~-s /CH ~

Step 3 OMe C14H130FS fw=248.32 A 12-liter, round-bottom flask was equipped with N2 gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3g/1.895mo1) and phenyl ether (2.Okg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temperature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425-9g/7.590mo1) was added, and the mixture was heated to reflux for 4 h. After cooling to room temperature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 L), and extracted with H20. The aqueous extracts were combined, acidified with concentrated HC1, and extracted with ethyl ether_ The ether extracts were dried (MgSO,), filtered, and concentrated in vacuo to give an amber oil (463.08, 98%
yield). 1H NMR confirmed desired structure.
Step 4 a~3 AN
OMe A 5-liter, 3-neck, round-bottom flask was equipped with N2 gas adaptor and mechanical stirrer. The system was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.Og/403.2mmo1) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0 C.
Sodium hydride (9.68g/383.2mmo1) was added slowly, and the mixture was allowed to warm to room temparature, 2,2-Dibutylpropylene sulfate (110.89g/443.6mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H20. The aqueous solution was washed with ethyl ether, and concentrated H2SOq was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ethex_ The ether solution was dried (MgSOq), filtered, and cone d in vacuo to give an amber oil (143.949/85 yield). 1H NNgt and MS [(M + H)+ = 419] confirm the desired structure.
Step 5 a~~
F
C25H3502FS fw=418.61 ., OMe A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor, and mechanical stirrer. The system was purged with N2. The corresponding alcohol (143.94g/343.8mmo1) and CH2C12 (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (140.53g/651.6mmol) was added. After 6 h., CH2C12 was added. After 20 min, the mixture was filtered through silica gel, washing with CH2C12. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.68, 77% yield). 1H NMR and MS ((M + H)+ = 417]
confirm the desired structure.
Step 6 oMs A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor and mechanical stirrer. The system was purged with N2. The corresponding sulfide ~1S
F
C25H33~2FS fw=416.59 C25H33~4FS fw=448.59 (110.6g/265.5m~nol) and CN2C12 (1.0 L) were added. The solution waa cooled to 0 C, and 3-chloroperbenzoic acid (158.21g/531.7mmo1) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to 0 C and filtered through a fine frizted funnel. The filtrate was washed with 10% aqueous R2C03. An emulsion formed which was extracted with ethyl ether. The oxganic layers were combined, dried IO (MgS04). filtered, and concenczated in vacuo to give the product (93.28. 78% yield). 1H Nit eonfizmed the desired stzucture.

Step 7 ' o ..
ow C2r~H33o4FS fw~d4B.59 A 2-liter, 4-neck, round-bottom flask was eguipped with N2 gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N2. The corresponding aldehyde (93.2g/208mmo1) and THE' (1.0 L) Were added. and the mixtuze was cooled to 0 C.
Potassium zerC-butoxide (23.35g/208.lmmol) was added via addition tunnel. After ih. 10% aq/ HCl (1.0 L) seas added. After 1 h, the mixture was extracted three times with ethyl ether, dried lMgSOa), filtered, and concentrated in vecuo. ?he crude product was purified by recryst. from 80!20 hexane/athyl acetate to give a white solid (32.18 gf. The mother liquor was concentrated in vacuo and rectystelized from 9515 toluene/ethyl acetate to give a white solid (33.60g/
combined yield: ?icy. 1N hHIt confirmed the desire3 product.

Step 8 o~
C27H390qNS fw=473.67 A Fisher porter bottle was fitted with N2 line and magnetic stirrer. The system was purged with N2. The corresponding fluoro-compound (28.1g/62.6mmo1) was added, and the vessel was sealed and cooled to -78 C.
Dimethylamine (1?.lg/379mmo1) was condensed via a C02/acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H20, saturated aqueous NaCl, dried (MgSOq), filtered, and concentrated in vacuo to give a white solid (28.Sg/96~ yield). 1H NMR
confirmed the desired structure.
~'1$

Step 9 ,o e~
off C26H3704NS fw=459.64 A 250-mL, 3-neck, round-bottom flask was equipped with N2 gas adaptor and magnetic stirrer. The system was purged with N2. The corresponding methoxy-compound (6.62g/l4.Ommo1) and CHC13 (150 mL) were added. The reaction mixture was cooled to -78 C, and boron tribromide (10.50g/41.9mmo1) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C and was quenched with 10% K2C03 (100 mL). After 10 mina the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHC13 and ether extracts were combined, washed with saturated aqueous NaCl, dried (MgS04), filtered, and concentrated in vacuo to give the product (6.27g/98% yield). 1H NMR confirmed the desired structure.
a~ 9 Step 10 (IijC~
8u to O
J
In a 250 ml single neck round bottom Flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172.1Og/mole) Aldrich D8, 720-1 (2.4 mmo1,4.12g), 34 ml dry ether and 34 ml of 1N ROH(agueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.
In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg , 2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product(previous step) 1.1 g (2.4 mmilomoles in 5 ml DMF and the ether solution prepared above. Heat to 40C for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms).The product may be further purified by chromatography (Si02 99% ethyl acetate/1% NH40H at 5m1/min.). Isolated yield: 0.78 g (mass spec , and H1 NMR) ~~ /o Step 11 _ ~~ //°
6u lu J'-The product from step 10 ( 0.57gms, 1.02 millimole fw 558.83 g/mole) and 1.6 gms iodoethane (10.02 mmol) was placed in S ml acetonitrile in a fischer-porter bottle and heated to 45 C for 3 days. The solution was evaporated to dryness and redissolved in 5 mls of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I = 587.9 , H NMR).
Fxamnle 1401 Step 1 OMe F
C14x13~2F fw=232.25 A 12-liter, 4-neck round-bottom flask was equipped with a81 reflux condenser. N2 gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N2.
A slurry of sodium hydride (126.Og/4.988mo1) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4-fluorophenol (560.5g/S.OOOmo1) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C) for lh. A solution of 3-methoxybenzyl chloride (783.Og/S.OOOmo1) in toluene (750 mL) was added via addition funnel while maintaining re.flux.
After 15 h. refluxing, the mixture was cooled to room temperature and poured into H20 (2.5 L). After 20 min.
stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720g) in MeOH (2.5 L). The MeOH layer was added to 20% aqueous potassium hydroxide, and the mixture was stirred for 30 min. The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aqueous KOH
solutions were combined and acidified with concentrated HC1. The acidic solution was extracted three times with ethyl ether, dried over MgS04, filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil (449.Og/39% yield). b.p.: 120-130 C/50mtorrHg.
1H NMR and MS ((M + H)+ = 233) confirmed desired structure.
Step 2 a~a-OMe F
C17H18N02FS fw=319.39 A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N2 gas adaptor. The system was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.Sg/1.961mo1) and dimethylformamide were added. The solution was cooled to 6 C, and sodium hydride (55.5g/2.197mo1) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4g/1.961mo1) was added. After 15 h, the reaction mixture was poured into H20 (4.0 L), and extracted two times with ethyl ether. The combined organic layers were washed with H20 and saturated aqueous NaCl, dried over MgS04, filtered, and concentrated in vacuo to give the product (605.3g, 97%
yield). 1H NMR and MS [(M+H)+ = 320 confirm desired structure.
Step 3 OMe ~~3 C1QH130FS fw=248.32 A 12-liter, round-bottom flask was equipped with N2 gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3g/1.895mo1) and phenyl ether (2.Okg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temperature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425.9g/7.594mo1) was added, and the mixture was heated to reflux for 4 h. After cooling to room temperature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 L), and extracted with H20. The aqueous extracts were combined, acidified with conc. HC1, and extracted with ethyl ether. The ether extracts were dried (MgSO,), filtered, and concentrated in vacuo to give an amber oil (463.Og, 98$
yield). 1H NMR confirmed desired structure.
Step 4 nN
OMe F
C25H3502FS fw=418.61 A 5-liter, 3-neck, round-bottom flask was equipped with N2 gas adaptor and mechanical stirrer. The system was purged With N2. 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.Og/403.2mmo1) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0 C.
Sodium hydride (9.68g/383.2mmo1) was added slowly, and the mixture was allowed to warm to room temperature 2,2-Dibutylpropylene sulfate (110.89g/443.6mmo1) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H20. The aqueous solution was washed with ethyl ether, and cone. H2S04 was added. The aqueous solution was heated to reflex for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgS04), filtered, and concentrated in vacuo to give an amber oil (143.94g/85%
yield). 1H NMR and MS [(M + H)+ = 419 confirm the desired structure.
Step 5 n OMe A 2-liter. 4-neck,~round-bottom flask was equipped with N2 gas adaptor, and mechanical stirrer.;,The system was purged with N2. The corresponding.alcohol (143.94 g/343.8 mmol) and CH2C12 (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (140.53g/651.6mmo1) was added. After 6 h., CH2C12 was ~$S
C25H3302FS fw=416.59 added. After 20 min, the mixture was filtered through silica gel, washing with CH2C12. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.68, 77% yield). 1H NMR and MS [(M + H)+ = 417) confirm the desired structure.
age Step 6 our C25H3304FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor and mechanical stirrer. The system was purged with N2. The correspona~ng 5u~ly~..=
(110.6g/265.5mmo1) and CH2C12 (1.0 L) were added. The solution was cooled to 0 C, and 3-chloroperbenzoic acid (158.21g/531.7mmo1) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to 0 C and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K2C03. An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgSOq), filtered, and concentrated in vacuo to give the product (93.2g, 78% yield). 1H NMR confirmed the desired structure.
a~~

Step 7 o~ll eu OH
s ~l a oM.
C25H33~4FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N2. The corresponding aldehyde (93.2g/208mmo1) and THF (1.0 L) were added, and the mixture was cooled to 0 C.
Potassium tert-butoxide (23.35g/208.1mmo1) was added via addition funnel. After lh, 10% aq/ HC1 (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgS04), filtered, and concentrated in vacuo. The crude product was purified by recrystallized from 80/20 hexane/ethyl acetate to give a white solid (32.18g). The mother liquor was concentrated in vacuo and recrystallized from 95/5 toluene/ethyl acetate to give a white solid (33.608, combined yield: 71%). 1H NMR confirmed the desired product.
$g Step 8 e~
C27H3904NS fw=473.67 A Fisher porter bottle was fitted with N2 line and magnetic stirrer. The system was purged with N2. The corresponding fluoro-compound (28.1g/62.6mmo1) was added, and the vessel was sealed and cooled to -78 C.
Dimethylamine (l7.lg/379mmo1) was condensed via a C02/acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H20, saturated aqueous NaCl, dried over MgS04, filtered, and concentrated in vacuo to give a white solid (28.Sg/96% yield). 1H NMR
confirmed the desired structure.
aeq Step 9 o a ju eu Me 2N
A 250-mL, 3-neck, round-bottom flask was equipped with N2 gas adaptor and magnetic stirrer. The system was purged with N2. The corresponding methoxy-compound (6.62g/l4.Ommo1) and CHC13 (150 mL) were added. The reaction mixture was cooled to -78 C, and boron tribromide (10.50g/41.9mmo1) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C and was quenched with 10$ K2C03 (100 mL). After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHC13 and ether extracts were combined, washed with saturated aqueous NaCl, . dried over MgS04, filtered, and concentrated in vacuo to give the product (6.27g/98% yield). ~~1H NMR
confirmed the desired structure.
~9 O
OH
c26H3704N~ fw=459.64 Step 10 Bu ' 3u J
In a 250 ml single neck round bottom flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172.1Og/mole) Aldrich D8, 720-1 (2.4 millimoles, 4.12g), 34 ml dry ether and 34 ml of 1N KOH
(aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.
In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg, (2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product (previous step) 1.1 g (2.4 mmol in 5 ml DMF and the ether solution prepared above. Heat to 40C for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5%
NaOH, followed by water and then brine. The ether layer was dried over Magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms). The product may be further purified by chromatography (silica 99% ethyl acetate/1% NH40H at 5m1/min..).
Isolated yield: 0.78 g (mass spec , and H1 NMR) Step 11 aq c Bu 3u J'-The product from step 10 (0.57gms, 1.02 millimole fw 558.83 g/mole) and iodoethane (1.6 gms (10.02 mmol)was place in 5 ml acetonitrile in a Fischer-Porter bottle and heated to 45 C for 3 days. The solution was evaporated to dryness and redissolved in 5 mls of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I = 587.9, 1H NMR).
BIOLOGICAL ASSAYS
The utility of the compounds of the present invention is shown by the following assays. These assays are performed in vitro and in animal models essentially using a procedure recognized to show the utility of the present invention.
In Vitro Assay of compounds that inhibit IHAT-mediated uptake of Iz~C1-Taurocholate lTC) in H14 Cells Baby hamster kidney cells (BIiK) transfected with the cDNA of human IBAT (H14 cells) are seeded-at 60,000 cells/well in 96 well Top-Count tissue culture plates for assays run within in 24 hours of seeding, 30,000 ag ~

cells/well for assays run within 48 hours, and 10,000 cells/well for assays run within ?2 hours.
On the day of assay, the cell monolayer is gently washed once with 100 ml assay buffer (Dulbecco's Modified Eagle's medium with 4.5 g/L glucose + 0.2~
_ (w/v) fatty acid free bovine serum albumin- (FAF)BSA).
To each well 50 ml of a two-fold concentrate of test compound in assay buffer is added along with 50 ml of 6 mM [1'C]-taurocholate in assay buffer (final concentration of 3 mM [1'C]-taurocholate). The cell culture plates are incubated 2 hours at 3?° C prior to gently washing each well twice with 100 ml 4° C
Dulbecco's phosphate-buffered saline (PBS) containing 0.2~ (w/v) (FAF)BSA. The wells are then gently washed once with 100 ml 4° C PBS without (FAF)BSA. To each 200 ml of liquid scintillation counting fluid is added, the plates are heat sealed and shaken for 30 minutes at room temperature prior to measuring the amount of radioactivity in each well on a Packard Top-Count instrument.
~~i 3 In Vitro Assa of com ounds that inhibit a take of j"C~-Alanine The alanine uptake assay is performed in an identical fashion to the taurocholate assay, with the exception that labeled alanine is substituted for the labeled taurocholate.
In yivo Assa of com ounds that inhibit Rat Ileal a take of I"Cl-Taurocholate into Hile (See"Metabolism of 3a,7b-dihydroxy-7a-methyl-5b-cholanoic acid and 3a,7b-dihydroxy-7a-methyl-5b-cholanoic acid in hamsters" in Biochimica et Biophysica Acta 833 (1985) 196-202 by Une et al.) Male wistar rats (200-300 g) are anesthetized with inactin @100 mg/kg. Bile ducts are cannulated with a 10" length of PE10 tubing. The small intestine is exposed and laid out on a gauze pad. A canulae (1/8"
luer lock, tapered female adapter) is inserted at 12 cm from the junction of the small intestine and the cecum.
A slit is cut at 4 cm from this same junction (utilizing a 8 cm length of ileum). 20 ml of warm Dulbecco's phosphate buffered saline, pH 6.5 (PBS) is used to flush out the intestine segment. The distal opening is cannulated with a 20 cm length of silicone tubing (0.02" I.D. x 0.037" O.D.). The proximal cannulae is hooked up to a peristaltic pump and the intestine is washed for 20 min with warm PBS at 0.25 ml/min. Temperature of the gut segment is monitored continuously. At the start of the experiment. 2.0 ml of control sample (["C]-taurocholate @ 0.05 mi/ml with 5 mM cold taurocholate) is loaded into the gut segment with a 3 ml syringe and,bile sample collection is begun. Control sample is infused at a rate of 0.25 ml/min for 21 min. Bile samples fractions are collected every 3 minute for the first 27 minutes of the procedure. After the 21 min of sample infusion, the ileal loop is washed out with 20 ml of warm PBS
(using a 30 ml syringe), and then the loop is washed out for 21 min with warm PBS at 0.25 ml/min. A second ~9 ~

perfusion is initiated as described above but this with test compound being administered as well (21 min administration followed by 21 min of wash out) and bile - sampled every 3 min for the first 27 min. If necessary, a third perfusion is performed as above that typically contains the control sample.
Measurement of Hepatic Cholesterol Concentration (HEPATIC CHOL) Liver tissue was weighed and homogenized in chloroform:methanol (2:1). After homogenization and centrifugation the supernatant was separated and dried under nitrogen. The residue was dissolved in is.opropanol and the cholesterol content was measured enzymatically, using a combination of cholesterol oxidase and peroxidase, as described by Allain, C. A., et a1. (1974) Clin. Chem. 2~, 470.
Measurement of Hepatic HMG CoA-Reductase Activity (HMG
COA
Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for HMG CoA reductase activity by incubating for 60 minutes at 37° C in the presence of "C-HMG-CoA (Dupont-NEN). The reaction was stopped by adding 6N HC1 followed by centrifugation. An aliquot of the supernatant was separated, by thin-layer chromatography, and the spot corresponding to the enzyme product was scraped off the plate, extracted and radioactivity was determined by scintillation counting.
(Reference: Akerlund, J. and Bjorkhem, I. (1990) J.
Lipid Res: 31, 2159).
Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL
TGI an8 VLDL + LDL) Total serum cholesterol (SER.CHOL) was measured enzymatically using a commercial kit from Wako Fine x.95 Chemicals (Richmond, VA); Cholesterol C11, Catalog No.
276-64909. HDL cholesterol (HDL-CHOL) was assayed using this same kit after precipitation of VLDL and LDL
with Sigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) were assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. VLDL and LDL (VLDL + LDL) cholesterol concentrations were calculated as the difference between total and HDL cholesterol.
Measurement of Hepatic Cholesterol 7-a-Hvdroxvlase Activitv (7a-OHase) Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for cholesterol 7-a-hydroxylase activity by incubating for 5 minutes at 37° C in the presence of NADPH.
Following extraction into petroleum ether, the organic solvent was evaporated and the residue was dissolved in acetonitrile/ methanol. The enzymatic product was separated by injecting an aliquot of the extract onto a Cl, reversed phase HPLC column and quantitating the eluted material using W detection at 240nm.
(Reference: Horton, J. D., et a1. (1994) J. Clin.
Invest. 93, 2084).
Measurement of Fecal Bile Acid Concentration (FBA
Total fecal output from individually housed hamsters was collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed.
Approximately 0.1 gram was weighed out and extracted into an organic solvent (butanol/water). Following separation and drying, the residue was dissolved in methanol and the amount of bile acid present~was measured enzymatically using the 3a-hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (Reference: Mashige, F., et al. (1981) a~ ~

WO 98/40375 PCT/US98/03~92 Clin. Chem. 27, 1352).
j'H7taurocholate Uptake in Rabbit Hrush Border Membrane yesicles (BHMV) Rabbit Ileal brush border membranes were prepared from frozen ileal mucosa by the calcium precipitation method describe by Malathi et al. (Reference: (1979) Biochimica Biophysica Acta, 554, 259). The method for measuring taurocholate was essentially as described by Kramer et a1. (Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except the assay volume was 200 ul instead of 100 ul. Briefly, at room temperature a 190 ul solution containing 2uM ('H]-taurocholate(0.75 uCi), 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 was incubated for 5 sec with 10 ul of brush border membrane vesicles (60-120 pg protein). The incubation was initiated by the addition of the BBMV while vortexing and the reaction was stopped by the addition of 5 ml of ice cold buffer (20 mM Hepes-tris, 150 mM KC1) followed immediately by filtration through a nylon filter (0.2 um poze) and an additional 5 ml wash with stop buffer.
Acvl-CoA;cholesterol Acvl Transferase (ACAT) Hamster liver and rat intestinal microsomes were prepared from tissue as described previously (Reference: (1980) J. Biol. Chem. 255, 9098) and used as a source of ACAT enzyme. The assay consisted of a-2.0 ml incubation containing 24 ),1M Oleoyl-CoA (0.05 uCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25 $ BSA and 200 ug of microsomal protein. The assay was initiated by the addition of oleoyl-Cod. The reaction went for 5 min at 37° C and was terminated by the addition of 8.0 ml of chloroform/
methanol (2:1). To the extraction was added 125 ug of cholesterol oleate in chloroform methanol to'act as a carrier and the organic and aqueous phases of the extraction were separated by centrifugation after thorough vortexing. The chloroform phase was taken to a9'1 dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether (9:1). The amount of cholesterol ester formed was determined by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the TLC plate with a Packard instaimager.
Data from each of the noted compounds in the assays described above is as set forth in TABLES 5, 6, 7, and 8 as follows:
a9~

COMPOUND IC50 In vitro % % % of Control uM* Inhibition Inhibition Transport of TC in of TC of Alanine Rat Ileum @ O.lmM
Uptake @ Uptake @ #
100 uM # 100 uM #

Benzothiaze 2 0 45.4 +/- 0.7 pine=

4a 3 5a 34 Sb 40 0 72.9 5.4 @ 0.5 mM

4b 9 14b 18 14a 13 19a 0 19b 15 8a 41 Mixture of 69 8a and 8b Mixture of 6 9a and 9b 6a 5 6b ( ( 85 9a 5 0% @ 25 mM 53.7 +/- 3.9 Mixture of 13 6a and 20 Mixture of 0.8 14% @ 25 6d and l0a ~T~M

21a 37 21c 52 21b 45 6c 2 58_5 68.8 +/- 5.7 0.4 at 6d . 0.6 77.7 16.1 +/- 1.1 0.5 @ @
mM 30.2 +/-0.9 0.15 mM

7 5p 49.3 l0a 7 77.6 62.4 =/- 2.5 0.2 @
mM

lOb 15 68.6 25 0.1 4% @ 10 mM 26.0 +/- 3.3 26 2 31% @ 25 87.9 +/- 1.5 mM

27 5 7% @ 20 mM

2g g 31% @ 20mM

29 88 @ 50 mM

30 . 96 @ 50 mM

31 41 @ 50 mM

37 3 0% @ 5 mM

38 p,3 11% @ 5mM 20.6 +/- 5.7 40 ~ ~49 @ 50 mM

3oa t DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTS PARTIE DE CETTE DEMANDS OU CE BREVET
COMPREND PLUS D'UN TOME.
CEC! EST LE TOME ~ DE
NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPL1CATIONS/PAT~ntTS
THIS SECTION OF THE APPLlCATIONIPATF.NT CONTAINS MORE
THAN ONE VOLUME
. THIS IS VOLUME Ol=
' NOTE: For additional volumes-phase contact the Canadian Patent Ofifica . ~'

Claims

What Is Claimed Is:

1. A composition, comprising an ileal bile acid transport inhibitor and an HMG Co-A reductase inhibitor.

2. The composition of claim 1 wherein the HMG Co-A
reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin.

3. A pharmaceutical composition, comprising:
a first amount of an ileal bile acid transport inhibitor, and a second amount of an HMG Co-A reductase inhibitor, wherein said first and second amounts of said inhibitors together comprise an anti-hyperlipidemic condition effective amount of said inhibitors, and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition of claim 3 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin.

5. A combination therapy method for the prophylaxis or treatment of a hyperlipidemic condition in a mammal, comprising:
administering to said patient a first amount of an ileal bile-acid transport inhibitor, and administering to said patient a second amount of an HMG Co-A reductase inhibitor, wherein said first and second amounts of said inhibitors together comprise an anti-hyperlipidemic condition effective amount of said inhibitors.

6. The combination therapy method of claim 5 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin.